Mass Hierarchy, Mixing, CP-Violation and Higgs Decay---or Why Rotation is Good for Us

The idea of a rank-one rotating mass matrix (R2M2) is reviewed detailing how it leads to ready explanations both for the fermion mass hierarchy and for the distinctive mixing patterns between up and down fermion states, which can be and have been tested against experiment and shown to be fully consistent with existing data. Further, R2M2 is seen to offer, as by-products: (i) a new solution of the strong CP problem in QCD by linking the theta-angle there to the Kobayashi-Maskawa CP-violating phase in the CKM matrix, and (ii) some novel predictions of possible anomalies in Higgs decay observable in principle at the LHC. A special effort is made to answer some questions raised.Comment: 47 pages, 9 figure

On the Corner Elements of the CKM and PMNS Matrices

Recent experiments show that the top-right corner element ($U_{e3}$) of the PMNS, like that ($V_{ub}$) of the CKM, matrix is small but nonzero, and suggest further via unitarity that it is smaller than the bottom-left corner element ($U_{\tau 1}$), again as in the CKM case ($V_{ub} < V_{td}$). An attempt in explaining these facts would seem an excellent test for any model of the mixing phenomenon. Here, it is shown that if to the assumption of a universal rank-one mass matrix, long favoured by phenomenologists, one adds that this matrix rotates with scale, then it follows that (A) by inputting the mass ratios $m_c/m_t, m_s/m_b, m_\mu/m_\tau$, and $m_2/m_3$, (i) the corner elements are small but nonzero, (ii) $V_{ub} < V_{td}$, $U_{e 3} < U_{\tau 1}$, (iii) estimates result for the ratios $V_{ub}/V_{td}$ and $U_{e 3}/U_{\tau 1}$, and (B) by inputting further the experimental values of $V_{us}, V_{tb}$ and $U_{e2},U_{\mu 3}$, (iv) estimates result for the values of the corner elements themselves. All the inequalities and estimates obtained are consistent with present data to within expectation for the approximations made.Comment: 9 pages, 2 figures, updated with new experimental data and more detail

Performance of the MIND detector at a Neutrino Factory using realistic muon reconstruction

A Neutrino Factory producing an intense beam composed of nu_e(nubar_e) and nubar_mu(nu_mu) from muon decays has been shown to have the greatest sensitivity to the two currently unmeasured neutrino mixing parameters, theta_13 and delta_CP . Using the `wrong-sign muon' signal to measure nu_e to nu_mu(nubar_e to nubar_mu) oscillations in a 50 ktonne Magnetised Iron Neutrino Detector (MIND) sensitivity to delta_CP could be maintained down to small values of theta_13. However, the detector efficiencies used in previous studies were calculated assuming perfect pattern recognition. In this paper, MIND is re-assessed taking into account, for the first time, a realistic pattern recognition for the muon candidate. Reoptimisation of the analysis utilises a combination of methods, including a multivariate analysis similar to the one used in MINOS, to maintain high efficiency while suppressing backgrounds, ensuring that the signal selection efficiency and the background levels are comparable or better than the ones in previous analyses

Developing the Framed Standard Model

The framed standard model (FSM) suggested earlier, which incorporates the Higgs field and 3 fermion generations as part of the framed gauge theory structure, is here developed further to show that it gives both quarks and leptons hierarchical masses and mixing matrices akin to what is experimentally observed. Among its many distinguishing features which lead to the above results are (i) the vacuum is degenerate under a global $su(3)$ symmetry which plays the role of fermion generations, (ii) the fermion mass matrix is "universal", rank-one and rotates (changes its orientation in generation space) with changing scale $\mu$, (iii) the metric in generation space is scale-dependent too, and in general non-flat, (iv) the theta-angle term in the QCD action of topological origin gets transformed into the CP-violating phase of the CKM matrix for quarks, thus offering at the same time a solution to the strong CP problem.Comment: 53 Page

Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

IMPORTANCE: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. OBJECTIVE: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. DESIGN, SETTING, AND PARTICIPANTS: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). EXPOSURES: Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. MAIN OUTCOMES AND MEASURES: Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). RESULTS: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. CONCLUSIONS AND RELEVANCE: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD

Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease

Objective We aimed to test whether region-specific factors, including spatial expression patterns of the tau-encoding gene MAPT and regional levels of amyloid positron emission tomography (PET), enhance connectivity-based modeling of the spatial variability in tau-PET deposition in the Alzheimer disease (AD) spectrum. Methods We included 685 participants (395 amyloid-positive participants within AD spectrum and 290 amyloid-negative controls) with tau-PET and amyloid-PET from 3 studies (Alzheimer's Disease Neuroimaging Initiative, 18F-AV-1451-A05, and BioFINDER-1). Resting-state functional magnetic resonance imaging was obtained in healthy controls (n = 1,000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain-parcellation atlas superimposed onto all modalities, we obtained region of interest (ROI)-to-ROI functional connectivity, ROI-level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid-PET as predictors of group-averaged and individual tau-PET ROI values in amyloid-positive participants. Results Connectivity alone explained 21.8 to 39.2% (range across 3 studies) of the variance in tau-PET ROI values averaged across amyloid-positive participants. Stepwise addition of MAPT gene expression and amyloid-PET increased the proportion of explained variance to 30.2 to 46.0% and 45.0 to 49.9%, respectively. Similarly, for the prediction of patient-level tau-PET ROI values, combining all 3 predictors significantly improved the variability explained (mean adjusted R2 range across studies = 0.118–0.148, 0.156–0.196, and 0.251–0.333 for connectivity alone, connectivity plus MAPT expression, and all 3 modalities combined, respectively). Interpretation Across 3 study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD. ANN NEUROL 202

Electron neutrino tagging through tertiary lepton detection

We discuss an experimental technique aimed at tagging electron neutrinos in multi-GeV artificial sources on an event-by-event basis. It exploits in a novel manner calorimetric and tracking technologies developed in the framework of the LHC experiments and of rare kaon decay searches. The setup is suited for slow-extraction, moderate power beams and it is based on an instrumented decay tunnel equipped with tagging units that intercept secondary and tertiary leptons from the bulk of undecayed \pi^+ and protons. We show that the taggers are able to reduce the \nue contamination originating from K_e3 decays by about one order of magnitude. Only a limited suppression (~60%) is achieved for \nue produced by the decay-in-flight of muons; for low beam powers, similar performance as for K_e3 can be reached supplementing the tagging system with an instrumented beam dump.Comment: 19 pages, 7 figures; minor changes, version to appear in EPJ

Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations

Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan

An improved measurement of muon antineutrino disappearance in MINOS

We report an improved measurement of muon anti-neutrino disappearance over a distance of 735km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a muon anti-neutrino enhanced configuration. From a total exposure of 2.95e20 protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of the anti-neutrino "atmospheric" delta-m squared = 2.62 +0.31/-0.28 (stat.) +/- 0.09 (syst.) and constrain the anti-neutrino atmospheric mixing angle >0.75 (90%CL). These values are in agreement with those measured for muon neutrinos, removing the tension reported previously.Comment: 5 pages, 4 figures. In submission to Phys.Rev.Let

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We employed a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicenter study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease-dementia with baseline [18F]flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences