Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT(2)R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies

BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT(2)R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT(2)R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT(2)R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT(2)R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging. RESULTS: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT(2)R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine. CONCLUSION: The major AT(2)R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways

Nociceptin/Orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons

The Nociceptin/Orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand Nociceptin/Orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry, and assessed functional effects of NOP and [micro] opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder sub-urothelium revealed a remarkable several-fold increase in Detrusor Overactivity (p<0.0001) and Painful Bladder Syndrome patient specimens (p=0.0014), compared to controls. In post-mortem control human DRGs, 75-80% of small/medium neurons (<=50 [micro]m diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP-immunoreactivity was significantly decreased in injured peripheral nerves (p=0.0004), and also in painful neuromas (p=0.025). Calcium imaging studies in cultured rat DRG neurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (p<0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than [mu]-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials

The onset of chaos in orbital pilot-wave dynamics

We present the results of a numerical investigation of the emergence of chaos in the orbital dynamics of droplets walking on a vertically vibrating fluid bath and acted upon by one of the three different external forces, specifically, Coriolis, Coulomb, or linear spring forces. As the vibrational forcing of the bath is increased progressively, circular orbits destabilize into wobbling orbits and eventually chaotic trajectories. We demonstrate that the route to chaos depends on the form of the external force. When acted upon by Coriolis or Coulomb forces, the droplet's orbital motion becomes chaotic through a period-doubling cascade. In the presence of a central harmonic potential, the transition to chaos follows a path reminiscent of the Ruelle-Takens-Newhouse scenario

Orbiting pairs of walking droplets: Dynamics and stability

A decade ago, Couder and Fort [Phys. Rev. Lett. 97, 154101 (2006)]PRLTAO0031-900710.1103/PhysRevLett.97.154101 discovered that a millimetric droplet sustained on the surface of a vibrating fluid bath may self-propel through a resonant interaction with its own wave field. We here present the results of a combined experimental and theoretical investigation of the interactions of such walking droplets. Specifically, we delimit experimentally the different regimes for an orbiting pair of identical walkers and extend the theoretical model of Oza [J. Fluid Mech. 737, 552 (2013)] JFLSA70022-112010.1017/jfm.2013.581 in order to rationalize our observations. A quantitative comparison between experiment and theory highlights the importance of spatial damping of the wave field. Our results also indicate that walkers adapt their impact phase according to the local wave height, an effect that stabilizes orbiting bound states.National Science Foundation (U.S.) (Grant CMMI-1333242)National Science Foundation (U.S.) (Grant DMS-1614043

Ferromagnetic Ordering in CeIr2B2: Transport, magnetization, specific heat and NMR studies

We present a complete characterization of ferromagnetic system CeIr2B2 using powder x-ray diffraction XRD, magnetic susceptibility chi(T), isothermal magnetization M(H), specific heat C(T), electrical resistivity rho(T,H), and thermoelectric power S(T) measurements. Furthermore 11B NMR study was performed to probe the magnetism on a microscopic scale. The chi(T), C(T) and rho(T) data confirm bulk ferromagnetic ordering with Tc = 5.1 K. Ce ions in CeIr2B2 are in stable trivalent state. Our low-temperature C(T) data measured down to 0.4 K yield Sommerfeld coefficient gamma = 73(4) mJ/molK2 which is much smaller than the previously reported value of gamma = 180 mJ/molK2 deduced from the specific heat measurement down to 2.5 K. For LaIr2B2 gamma = 6(1) mJ/molK2 which implies the density of states at the Fermi level D(EF) = 2.54 states/(eV f.u.) for both spin directions. The renormalization factor for quasi-particle density of states and hence for quasi-particle mass due to 4f correlations in CeIr2B2 is 12. The Kondo temperature TK ~ 4 K is estimated from the jump in specific heat of CeIr2B2 at Tc. Both C(T) and rho(T) data exhibit gapped-magnon behavior in magnetically ordered state with an energy gap Eg ~ 3.5 K. The rho data as a function of magnetic field H indicate a large negative magnetoresistance (MR) which is highest for T = 5 K.While at 5 K the negative MR keeps on increasing up to 10 T, at 2 K an upturn is observed near H = 3.5 T. On the other hand, the thermoelectric power data have small absolute values (S ~ 7 {\mu}V/K) indicating a weak Kondo interaction. A shoulder in S(T) at about 30 K followed by a minimum at ~ 10 K is attributed to crystal electric field (CEF) effects and the onset of magnetic ordering. 11B NMR line broadening provides strong evidence of ferromagnetic correlations below 40 K.Comment: 10 pages, 11 figure

Moduli-Space Dynamics of Noncommutative Abelian Sigma-Model Solitons

In the noncommutative (Moyal) plane, we relate exact U(1) sigma-model solitons to generic scalar-field solitons for an infinitely stiff potential. The static k-lump moduli space C^k/S_k features a natural K"ahler metric induced from an embedding Grassmannian. The moduli-space dynamics is blind against adding a WZW-like term to the sigma-model action and thus also applies to the integrable U(1) Ward model. For the latter's two-soliton motion we compare the exact field configurations with their supposed moduli-space approximations. Surprisingly, the two do not match, which questions the adiabatic method for noncommutative solitons.Comment: 1+15 pages, 2 figures; v2: reference added, to appear in JHE

Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia

Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel {beta} subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(-/-) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis

A stochastic flow rule for granular materials

There have been many attempts to derive continuum models for dense granular flow, but a general theory is still lacking. Here, we start with Mohr-Coulomb plasticity for quasi-2D granular materials to calculate (average) stresses and slip planes, but we propose a "stochastic flow rule" (SFR) to replace the principle of coaxiality in classical plasticity. The SFR takes into account two crucial features of granular materials - discreteness and randomness - via diffusing "spots" of local fluidization, which act as carriers of plasticity. We postulate that spots perform random walks biased along slip-lines with a drift direction determined by the stress imbalance upon a local switch from static to dynamic friction. In the continuum limit (based on a Fokker-Planck equation for the spot concentration), this simple model is able to predict a variety of granular flow profiles in flat-bottom silos, annular Couette cells, flowing heaps, and plate-dragging experiments -- with essentially no fitting parameters -- although it is only expected to function where material is at incipient failure and slip-lines are inadmissible. For special cases of admissible slip-lines, such as plate dragging under a heavy load or flow down an inclined plane, we postulate a transition to rate-dependent Bagnold rheology, where flow occurs by sliding shear planes. With different yield criteria, the SFR provides a general framework for multiscale modeling of plasticity in amorphous materials, cycling between continuum limit-state stress calculations, meso-scale spot random walks, and microscopic particle relaxation

SUPPORTIVE THERAPY: AN OPTION TO ENHANCE HOST IMMUNITY AGAINST COVID-19

The threat posed by COVID 19 outbreak, which is considered to be a global pandemic, is immeasurably affecting all the communities worldwide. COVID-19 is a zoonotic disease, which can affect birds, humans and, other animals. The emergence of this pandemic has been creating a tragic situation worldwide by affecting more people through human-human transmission. The burden (both healthwise and economic) placed by the disease is so huge that any measures to improve the current situation, to fasten up the recovery of already affected patients and, to reduce the risk of death and health deterioration should be considered. Vaccination, being the hope in the scenario, helps in preventing the condition to an extent, but in the absence of availability of a proper drug regimen to fight off COVID 19, the requirement of the need to find a system to control the severity of the infection is a necessity Nutritional supplementation helps in boosting up the immune system especially, vitamins like vitamin C, Vitamin D, Zinc, Omega 3 fatty acids, etc. They also exhibit established immunomodulatory, antiviral as well as anti-inflammatory effects. Pieces of evidence have also highlighted the importance of supportive therapy using nutrient supplements in covid patients as it helps in prominent decreasing of SARS CoV2 load of the virus and also significantly reduces the hospitalization period. Hence the nutritional levels of each of the infected person must be assessed before initiating the anti-viral therapy. The search criteria used were PubMed, Medscape, google scholar, etc. The keywords used to search were COVID 19 Supportive therapy, Vitamin D, Vitamin C, Nutrient supplementation, Host immunity, etc. The range of years is between 1978 and 2021