Custodial SO(4) symmetry and CP violation in N-Higgs-doublet potentials

We study the implementation of global $SO(4)\sim SU(2)_L\otimes SU(2)_R$ symmetry in general potentials with N-Higgs-doublets in order to obtain models with custodial $SO(3)_C$ symmetry. We conclude that any implementation of the custodial SO(4) symmetry is equivalent, by a basis transformation, to a canonical one if $SU(2)_L$ is the gauge factor, $U(1)_Y$ is embedded in $SU(2)_R$ and we require $N$ copies of the doublet representation of $SU(2)_R$. The invariance by SO(4) automatically leads to a CP invariant potential and the basis of the canonical implementation of SO(4) is aligned to a basis where CP-symmetry acts in the standard fashion. We show different but equivalent implementations for the 2HDM, including an implementation not previously considered.Comment: 22pp, REVTeX4. Published versio

Differential Expression Of Gap Junction mRNAs And Proteins In The Developing Murine Kidney And In Experimentally Induced Nephric Mesenchymes

The expression of three gap junction (GJ) proteins, alpha-1 (Cx43), beta-1 (Cx32), and beta-2 (Cx26), and their transcripts were examined during the ontogeny of the mouse and rat kidney. These proteins were expressed in two non-overlapping patterns. The alpha-1 GJ protein was first observed in mesenchymal cells in the 12-day mouse kidney. By day 14 and thereafter, the ai protein was detected in the transient S-shaped bodies, but not in the podocytes of the maturing glomeruli. After birth the antigen was retained in a small subset of secretory tubules.The beta-1 and beta-2 GJ proteins were similar in their developmental patterns. They were first detected in a small subset of secretory tubules in the subcortical zone of day 17 embryos. These tubules were identified by immunohistochemical markers to be proximal. At birth, practically all proximal tubules expressed the two antigens.This analysis of GJ proteins was consistent with the results of S1 nuclease protection assays showing that, while the alpha-1 mRNA appeared early during kidney development and declined around birth, the two beta mRNAs appeared later and became intensified during the last days of intrauterine development.In experimentally induced metanephric mesenchymes, a transient expression of the alpha-1 GJ protein was seen during the segregation of the tubular anlagen. beta-1 and beta-2 GJ proteins were not detected in such induced mesenchymes cultivated up to 7 days.These observations provide evidence for the cell-specific utilization of different GJ genes during different stages of kidney organogenesis. The alpha-1 gene is activated during the early segregation of the secretory tubule and might contribute to its compartmentalization, while the beta-1 and beta-2 gene products are not detected until advanced stages of development. The latter gene products might be correlated with the physiological activity of the proximal tubules in vivo, as they are not expressed in experimentally induced tubules detectable with markers for proximal tubules

Magnetic Field-Induced Superconductor-Insulator-Metal Transition in an Organic Conductor: An Infrared Magneto-Optical Imaging Spectroscopy

The magnetic field-induced superconductor-insulator-metal transition (SIMT) in partially deuterated $\kappa$-(BEDT-TTF)$_2$Cu[N(CN)$_2$]Br, which is just on the Mott boundary, has been observed using the infrared magneto-optical imaging spectroscopy. The infrared reflectivity image on the sample surface revealed that the metallic (or superconducting) and insulating phases coexist and they have different magnetic field dependences. One of the magnetic field dependence is SIMT that appeared on part of the sample surface. The SIMT was concluded to originate from the balance of the inhomogenity in the sample itself and the disorder of the ethylene end groups resulting from fast cooling.Comment: 5 pages, 5 figures, to appear in Phys. Rev.

CP violation in the lepton sector and implications for leptogenesis

We review the current status of the data on neutrino masses and lepton mixing and the prospects for measuring the CP-violating phases in the lepton sector. The possible connection between low energy CP violation encoded in the Dirac and Majorana phases of the Pontecorvo-Maki-Nakagawa-Sakata mixing matrix and successful leptogenesis is emphasized in the context of seesaw extensions of the Standard Model with a flavor symmetry Gf (and CP symmetry)

Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.

Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis

Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

BACKGROUND: Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. METHODS: We investigated the effects of androgen on glycogen phosphorylase (GP), glycogen synthase (GS) and on glycogen accumulation in the androgen-receptor (AR) reconstituted PC3 cell line containing either an empty vector (PC3-AR-V) or vector with HPV-E7 (PC3-AR-E7) and the LNCaP cell line. RESULTS: Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P) had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. CONCLUSION: Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence

Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation.

Background: Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies. Methods: MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high. Results: Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.22, with 12/21 reporting a statistically significant protective effect and none a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding. Conclusions: Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk

Adverse childhood experiences and the development of multimorbidity across adulthood—a national 70-year cohort study

AIM: To examine impact of adverse childhood experiences (ACE) on rates and development of multimorbidity across three decades in adulthood. METHODS: Sample: Participants from the 1946 National Survey of Health and Development, who attended the age 36 assessment in 1982 and follow-up assessments (ages 43, 53, 63, 69; N = 3,264, 51% males). Prospectively collected data on nine ACEs was grouped into (i) psychosocial, (ii) parental health and (iii) childhood health. For each group, we calculated cumulative ACE scores, categorised into 0, 1 and ≥2 ACEs. Multimorbidity was estimated as the total score of 18 health disorders.Serial cross-sectional linear regression was used to estimate associations between grouped ACEs and multimorbidity during follow-up. Longitudinal analysis of ACE-associated changes in multimorbidity trajectories across follow-up was estimated using linear mixed-effects modelling for ACE groups (adjusted for sex and childhood socioeconomic circumstances). FINDINGS: Accumulation of psychosocial and childhood health ACEs were associated with progressively higher multimorbidity scores throughout follow-up. For example, those with ≥2 psychosocial ACEs experienced 0.20(95% CI 0.07, 0.34) more disorders at age 36 than those with none, rising to 0.61(0.18, 1.04) disorders at age 69.All three grouped ACEs were associated with greater rates of accumulation and higher multimorbidity trajectories across adulthood. For example, individuals with ≥2 psychosocial ACEs developed 0.13(-0.09, 0.34) more disorders between ages 36 and 43, 0.29(0.06, 0.52) disorders between ages 53 and 63, and 0.30(0.09, 0.52) disorders between ages 63 and 69 compared with no psychosocial ACEs. INTERPRETATIONS: ACEs are associated with widening inequalities in multimorbidity development in adulthood and early old age. Public health policies should aim to reduce these disparities through individual and population-level interventions

Symmetry and dimension of the magnon dispersion of inorganic spin-Peierls systems

The data on the dispersion of the magnetic excitations of CuGeO_3 in the spin-Peierls dimerized phase are analyzed. On the basis of the lattice structure it is shown that even along the chains the $d=2$ character cannot be neglected. The symmetry of the dispersion differs from the one assumed so far. The magnetic resonance data is reinterpreted. The possibility of interchain rather than intrachain frustration is discussed.Comment: 4 pages, Revtex, to appear in PR