Recovering the Principle of Relativity from the Cosmic Fabric Model of Space

We extend the descriptive power of the Cosmic Fabric model of space developed by Tenev and Horstemeyer (2018) to include moving observers by demonstrating that all reference frames are phenomenologically equivalent with one another and transform between each other via the Lorentz transformations. Our approach is similar to that of Lorentz (1892), which was used to explain the negative outcome of the Michelson-Morley {\ae}ther detection experiment (Michelson and Morley 1887), except that we deduce the notions of length contraction and time dilation from the postulates of the Cosmic Fabric model. Our result is valid for the continuum length scale at which, by definition, the cosmic fabric can be described mathematically as a continuum. Herein, we also discuss the length-scale dependent nature of the Cosmic Fabric model as a possible way to relate gravitational and quantum theories

Dual A 1 /A 2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction

ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A 1 /A 2B adenosine receptor blockade is beneficial in obese ZSF 1 rats, an animal model of HFpEF with metabolic syndrome. The combined A 1 /A 2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF 1 rats (n 5 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF 1 rats (n 5 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 6 550; BG9928 group, 2900 6 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 6 179; BG9928 group, 196 6 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/ day: control group, 1702 6 263; BG9928 group, 1076 6 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A 1/ A 2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A 1/ A 2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Dialysis delivery of an adenosine A 2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep

In vivo microdialysis in C57BL/6J (B6) mouse was used to test the hypothesis that activating adenosine A 2A receptors in the pontine reticular formation (PRF) increases acetylcholine (ACh) release and rapid eye movement (REM) sleep. Eight concentrations of the adenosine A 2A receptor agonist 2- p- (2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; CGS) were delivered to the PRF and ACh in the PRF was quantified. ACh release was significantly increased by dialysis with 3 μm CGS and significantly decreased by dialysis with 10 and 100 μm CGS. Co-administration of the adenosine A 2A receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 30 nm) blocked the CGS-induced increase in ACh release. In a second series of experiments, CGS (3 μm) was delivered by dialysis to the PRF for 2 h while recording sleep and wakefulness. CGS significantly decreased time in wakefulness (−51% in h 1; −54% in h 2), increased time in non-rapid eye movement (NREM) sleep (90% in h 1; 151% in h 2), and increased both time in REM sleep (331% in h 2) and the number of REM sleep episodes (488% in h 2). The enhancement of REM sleep is consistent with the interpretation that adenosine A 2A receptors in the PRF of the B6 mouse contribute to REM sleep regulation, in part, by increasing ACh release in the PRF. A 2A receptor activation may promote NREM sleep via GABAergic inhibition of arousal promoting neurons in the PRF.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66018/1/j.1471-4159.2006.03700.x.pd

Irreversible Quantum Mechanics in the Neutral K-System

The neutral Kaon system is used to test the quantum theory of resonance scattering and decay phenomena. The two dimensional Lee-Oehme-Yang theory with complex Hamiltonian is obtained by truncating the complex basis vector expansion of the exact theory in Rigged Hilbert space. This can be done for K_1 and K_2 as well as for K_S and K_L, depending upon whether one chooses the (self-adjoint, semi-bounded) Hamiltonian as commuting or non-commuting with CP. As an unexpected curiosity one can show that the exact theory (without truncation) predicts long-time 2 pion decays of the neutral Kaon system even if the Hamiltonian conserves CP.Comment: 36 pages, 1 PostScript figure include

Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance.

BACKGROUND: Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF). METHODS AND RESULTS: We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a > or =25% and a > or =0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%). RESULTS: Patients were followed for 480+/-363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13-1.81; p=0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p=0.002), LV ejection fraction (p=0.012), furosemide daily dose (p=0.03) and NYHA class (p=0.05) on admission. CONCLUSION: WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF

New polymorphisms associated with response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis

Anti-tumor necrosis factor (anti-TNF) drugs are effective against psoriasis, although 20–30% of patients are nonresponders. Few pharmacogenomic studies have been performed to predict the response to anti-TNF drugs in psoriasis. We studied 173 polymorphisms to establish an association with the response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis (N=144). We evaluated the response using PASI75 at 3, 6 and 12 months. The results of the multivariate analysis showed an association between polymorphisms in PGLYR4, ZNF816A, CTNNA2, IL12B, MAP3K1 and HLA-C genes and the response at 3 months. Besides, the results for polymorphisms in IL12B and MAP3K1 were replicated at 6 months. We also obtained significant results for IL12B polymorphism at 1 year. Moreover, polymorphisms in FCGR2A, HTR2A and CDKAL1 were significant at 6 months. This is the first study to show an association with these polymorphisms. However, these biomarkers should be validated in large-scale studies before implementation in clinical practiceThis study was supported by Instituto de Salud Carlos III (FIS PI10/01740), Fundación Teófilo Hernando, and AbbVie. RPP has a grant from Universidad Autónoma de Madrid (FPI program 2013

Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2

SummaryMicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 “seed matches” and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets