The Littlest Higgs in Anti-de Sitter Space

We implement the SU(5)/SO(5) littlest Higgs theory in a slice of 5D Anti-de Sitter space bounded by a UV brane and an IR brane. In this model, there is a bulk SU(5) gauge symmetry that is broken to SO(5) on the IR brane, and the Higgs boson is contained in the Goldstones from this breaking. All of the interactions on the IR brane preserve the global symmetries that protect the Higgs mass, but a radiative potential is generated through loops that stretch to the UV brane where there are explicit SU(5) violating boundary conditions. Like the original littlest Higgs, this model exhibits collective breaking in that two interactions must be turned on in order to generate a Higgs potential. In AdS space, however, collective breaking does not appear in coupling constants directly but rather in the choice of UV brane boundary conditions. We match this AdS construction to the known low energy structure of the littlest Higgs and comment on some of the tensions inherent in the AdS construction. We calculate the 5D Coleman-Weinberg effective potential for the Higgs and find that collective breaking is manifest. In a simplified model with only the SU(2) gauge structure and the top quark, the physical Higgs mass can be of order 200 GeV with no considerable fine tuning (25%). We sketch a more realistic model involving the entire gauge and fermion structure that also implements T-parity, and we comment on the tension between T-parity and flavor structure.Comment: 42 pages, 7 figures, 3 tables; v2: minor rewording, JHEP format; v3: to match JHEP versio

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Background and Purpose: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse-related measures and heroin versus food choice. Experimental Approach: For relapse assessment, we trained male and female rats to self-administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin-seeking in a non-drug Context B, (2) extinction responding reinforced by heroin-associated discrete cues in Context B, (3) reinstatement of heroin-seeking induced by re-exposure to Context A and (4) re-acquisition of heroin self-administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re-acquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications: Chronic BU08028 delivery had both beneficial and detrimental, sex-dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.</p

PAMELA, DAMA, INTEGRAL and Signatures of Metastable Excited WIMPs

Models of dark matter with ~ GeV scale force mediators provide attractive explanations of many high energy anomalies, including PAMELA, ATIC, and the WMAP haze. At the same time, by exploiting the ~ MeV scale excited states that are automatically present in such theories, these models naturally explain the DAMA/LIBRA and INTEGRAL signals through the inelastic dark matter (iDM) and exciting dark matter (XDM) scenarios, respectively. Interestingly, with only weak kinetic mixing to hypercharge to mediate decays, the lifetime of excited states with delta < 2 m_e is longer than the age of the universe. The fractional relic abundance of these excited states depends on the temperature of kinetic decoupling, but can be appreciable. There could easily be other mechanisms for rapid decay, but the consequences of such long-lived states are intriguing. We find that CDMS constrains the fractional relic population of ~100 keV states to be <~ 10^-2, for a 1 TeV WIMP with sigma_n = 10^-40 cm^2. Upcoming searches at CDMS, as well as xenon, silicon, and argon targets, can push this limit significantly lower. We also consider the possibility that the DAMA excitation occurs from a metastable state into the XDM state, which decays via e+e- emission, which allows lighter states to explain the INTEGRAL signal due to the small kinetic energies required. Such models yield dramatic signals from down-scattering, with spectra peaking at high energies, sometimes as high as ~1 MeV, well outside the usual search windows. Such signals would be visible at future Ar and Si experiments, and may be visible at Ge and Xe experiments. We also consider other XDM models involving ~ 500 keV metastable states, and find they can allow lighter WIMPs to explain INTEGRAL as well.Comment: 22 pages, 7 figure

Pharmacol Rev

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review pre-clinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinc-tion of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones’ role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women. The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not suffi-ciently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed pro-vide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue-or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. Significance Statement——This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed pro-vide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking. © 2022, American Society for Pharmacology and Experimental Therapy. All rights reserved

Pfsec13 is an unusual chromatin-associated nucleoporin of plasmodium falciparum that is essential for parasite proliferation in human erythrocytes

In Plasmodium falciparum, the deadliest form of human malaria, the nuclear periphery has drawn much attention due to its role as a subnuclear compartment involved in virulence gene expression. Recent data have implicated components of the nuclear envelope in regulating gene expression in several eukaryotes. Special attention has been given to nucleoporins that compose the nuclear pore complex (NPC). However, very little is known about components of the nuclear envelope in Plasmodium parasites. Here we characterize PfSec13, an unusual nucleoporin of P. falciparum, which shows unique structural similarities suggesting that it is a fusion between Sec13 and Nup145C of yeast. Using super resolution fluorescence microscopy (3D-SIM) and in vivo imaging, we show that the dynamiclocalization of PfSec13 during parasites' intra-erythrocytic development corresponds with that of the NPCs and that these dynamics are associated with microtubules rather than with F-actin. In addition, PfSec13 does not co-localize with the heterochormatin markers HP1 and H3K9me3, suggesting euchromatic location of the NPCs. The proteins associated with PfSec13 indicate that this unusual Nup is involved in several cellular processes. Indeed, ultrastructural and chromatin immunoprecipitation analyses revealed that, in addition to the NPCs, PfSec13 is found in the nucleoplasm where it is associated with chromatin. Finally, we used peptide nucleic acids (PNA) to downregulate PfSec13 and show that it is essential for parasite proliferation in human erythrocytes. © 2013. Published by The Company of Biologists Ltd

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min-1·1.73 m-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02065791

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. SIGNIFICANCE STATEMENT In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence