Large Time-dependent CP Violation in B_s^0 System and Finite D^0-D^0bar Mass Difference in Four Generation Standard Mode

Combining the measured B_s mixing with b \to s\ell^+\ell^- rate data, we find a sizable 4 generation t' quark effect is allowed, for example with m_{t'} \sim 300 GeV and V_{t's}^*V_{t'b} \sim 0.025 e^{\pm i 70^\circ}, which could underly the new physics indications in CP violation studies of b \to s qbar q transitions. With positive phase, large and negative mixing-dependent CP violation in B_s system is predicted, \sin 2\Phi_{B_s} \sim -0.5 to -0.7. This can also be probed via width difference methods. As a corollary, the short distance generated D^0-D^0bar mass difference is found to be consistent with, if not slightly higher than, recent B factory measurements, while CP violation is subdued with \sin 2\Phi_D \sim -0.2.Comment: 5 pages, 3 figures added (to total of 11 figures), revision to clarify b -> s photon contrast with Bs and D mixin

Cognition across the lifespan: Investigating age, sex, and other sociodemographic influences

Maintaining cognitive health across the lifespan has been the focus of a multi-billion-dollar industry. In order to guide treatment and interventions, a clear understanding of the way that proficiency in different cognitive domains develops and declines in both sexes across the lifespan is necessary. Additionally, there are sex differences in a range of other factors, including psychiatric illnesses such as anxiety, depression, and substance use, that are also known to affect cognition, although the scale of this interaction is unknown. Our objective was to assess differences in cognitive function across the lifespan in men and women in a large, representative sample. Leveraging online cognitive testing, a sample of 9451 men and 9451 women ranging in age from 12 to 69 (M = 28.21) matched on socio-demographic factors were studied. Segmented regression was used to model three cognitive domains—working memory, verbal abilities, and reasoning. Sex differences in all three domains were minimal; however, after broadening the sample in terms of socio-demographic factors, sex differences appeared. These results suggest that cognition across the lifespan differs for men and women, but is greatly influenced by environmental factors. We discuss these findings within a framework that describes sex differences in cognition as likely guided by a complex interplay between biology and environment

hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11a and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11a isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11a is involved in these resistance mechanisms. The specific hMENA11a depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11a phosphorylation and affected its localization. At the functional level, we found that hMENA11a sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11a silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11a contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11a in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11a expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA11a activity could represent a new target for antiproliferative therapies in breast cancer

The emergence of integrated information, complexity, and \u27consciousness\u27 at criticality

© 2020 by the authors. Integrated Information Theory (IIT) posits that integrated information (F) represents the quantity of a conscious experience. Here, the generalized Ising model was used to calculate F as a function of temperature in toy models of fully connected neural networks. A Monte-Carlo simulation was run on 159 normalized, random, positively weighted networks analogous to small five-node excitatory neural network motifs. Integrated information generated by this sample of small Ising models was measured across model parameter spaces. It was observed that integrated information, as an order parameter, underwent a phase transition at the critical point in the model. This critical point was demarcated by the peak of the generalized susceptibility (or variance in configuration due to temperature) of integrated information. At this critical point, integrated information was maximally receptive and responsive to perturbations of its own states. The results of this study provide evidence that F can capture integrated information in an empirical dataset, and display critical behavior acting as an order parameter from the generalized Ising model

Diffusion tensor imaging and white matter abnormalities in patients with disorders of consciousness.

Progress in neuroimaging has yielded new powerful tools which, potentially, can be applied to clinical populations, improve the diagnosis of neurological disorders and predict outcome. At present, the diagnosis of consciousness disorders is limited to subjective assessment and objective measurements of behavior, with an emerging role for neuroimaging techniques. In this review we focus on white matter alterations measured using Diffusion Tensor Imaging on patients with consciousness disorders, examining the most common diffusion imaging acquisition protocols and considering the main issues related to diffusion imaging analyses. We conclude by considering some of the remaining challenges to overcome, the existing knowledge gaps and the potential role of neuroimaging in understanding the pathogenesis and clinical features of disorders of consciousness

Role of Dimensionality in Predicting the Spontaneous Behavior of the Brain Using the Classical Ising Model and the Ising Model Implemented on a Structural Connectome

© Pubuditha M. Abeyasinghe et al. 2018. There is accumulating evidence that spontaneous fluctuations of the brain are sustained by a structural architecture of axonal fiber bundles. Various models have been used to investigate this structure-function relationship. In this work, we implemented the Ising model using the number of fibers between each pair of brain regions as input. The output of the Ising model simulations on a structural connectome was then compared with empirical functional connectivity data. A simpler two-dimensional classical Ising model was used as the baseline model for comparison purpose. Thermodynamic properties, such as the magnetic susceptibility and the specific heat, illustrated a phase transition from an ordered phase to a disordered phase at the critical temperature. Despite the differences between the two models, the lattice Ising model and the Ising model implemented on a structural connectome (the generalized Ising model) exhibited similar patterns of global properties. To study the behavior of the generalized Ising model around criticality, calculation of the dimensionality and critical exponents was performed for the first time, by introducing a new concept of distance based on structural connectivity. Same value inside the fitting error was found for the dimensionality in both models suggesting similar behavior of the models around criticality

Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation

Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule-severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy. However, until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient-derived cells, thus revealing novel therapeutic targets for the treatment of SPG4-HSP

Phenomenology of a Quark Mass Matrix from Six Dimensions and its implication for the Strong CP problem

A model of quark mass matrices from six dimensions, which is nearly democatic in nature and which is previously constructed by two of us (PQH and MS), is studied in detail in this manuscript. We found that not only it fits all the six quark masses as well as the CKM matrix but also that there exists a region in the allowed parameter space of the model where the constraint on the parameter \bar{\theta} of the Strong CP problem is satisfied. This region itself puts a constraint on the CKM parameters \bar{\rho} and \bar{\eta}. As such, through our analysis, there appears to be a deep connection between Strong and Weak CP in this modelComment: RevTeX, 21 pages and 14 figure

Wt-p53 action in human leukaemia cell lines corresponding to different stages of differentiation.

Recent studies support the potential application of the wt-p53 gene in cancer therapy. Expression of exogenous wt-p53 suppresses a variety of leukaemia phenotypes by acting on cell survival, proliferation and/or differentiation. As for tumour gene therapy, the final fate of the neoplastic cells is one of the most relevant points. We examined the effects of exogenous wt-p53 gene expression in several leukaemia cell lines to identify p53-responsive leukaemia. The temperature-sensitive p53Val135 mutant or the human wt-p53 cDNA was transduced in leukaemia cell lines representative of different acute leukaemia FAB subtypes, including M1 (KG1), M2 (HL-60), M3 (NB4), M5 (U937) and M6 (HEL 92.1.7), as well as blast crisis of chronic myelogenous leukaemia (BC-CML: K562, BV173) showing diverse differentiation features. By morphological, molecular and biochemical analyses, we have shown that exogenous wt-p53 gene expression induces apoptosis only in cells corresponding to M1, M2 and M3 of the FAB classification and in BC-CML showing morphological and cytochemical features of undifferentiated blast cells. In contrast, it promotes differentiation in the others. Interestingly, cell responsiveness was independent of the vector used and the status of the endogenous p53 gene