Endoplasmic reticulum degradation impedes olfactory G-protein coupled receptor functional expression

BACKGROUND: Research on olfactory G-protein coupled receptors (GPCRs) has been severely impeded by poor functional expression in heterologous systems. Previously, we demonstrated that inefficient olfactory receptor (OR) expression at the plasma membrane is attributable, in part, to degradation of endoplasmic reticulum (ER)-retained ORs by the ubiquitin-proteasome system and sequestration of ORs in ER aggregates that are degraded by autophagy. Thus, experiments were performed to test the hypothesis that attenuation of ER degradation improves OR functional expression in heterologous cells. RESULTS: To develop means to increase the functional expression of ORs, we devised an approach to measure activation of the mOREG OR (Unigene # Mm.196680; Olfr73) through coupling to an olfactory cyclic nucleotide-gated cation channel (CNG). This system, which utilizes signal transduction machinery coupled to OR activation in native olfactory sensory neurons, was used to demonstrate that degradation, both by the ubiquitin-proteasome system and autophagy, limits mOREG functional expression. The stimulatory effects of proteasome and autophagy inhibitors on mOREG function required export from the ER and trafficking through the biosynthetic pathway. CONCLUSIONS: These findings demonstrate that poor functional expression of mOREG in heterologous cells is improved by blocking proteolysis. Inhibition of ER degradation may improve the function of other ORs and assist future efforts to elucidate the molecular basis of odor discrimination

Synthesis and Evaluation of Thiochroman-4-One Derivatives as Potential Leishmanicidal Agents

ABSTARCT: The S-containing heterocyclic compounds benzothiopyrans or thiochromones stand out as having promising biological activities due to their structural relationship with chromones (benzopyrans), which are widely known as privileged scaffolds in medicinal chemistry. In this work, we report the synthesis of 35 thiochromone derivatives and the in vitro antileishmanial and cytotoxic activities. Compounds were tested against intracellular amastigotes of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Compounds bearing a vinyl sulfone moiety, 4h, 4i, 4j, 4k, 4l and 4m, displayed the highest antileishmanial activity, with EC50 values lower than 10 μM and an index of selectivity over 100 for compounds 4j and 4l. When the double bond or the sulfone moiety was removed, the activity decreased. Our results show that thiochromones bearing a vinyl sulfone moiety are endowed with high antileishmanial activity and low cytotoxicity

AP-1cFos/JunB/miR-200a regulate the pro-regenerative glial cell response during axolotl spinal cord regeneration

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sabin, Keith Z., Jiang, Peng, Gearhart, Micah D., Stewart, Ron, & Echeverri, Karen. AP-1cFos/JunB/miR-200a regulate the pro-regenerative glial cell response during axolotl spinal cord regeneration. Communications Biology, 2(91), (2019), doi:10.1038/s42003-019-0335-4.Salamanders have the remarkable ability to functionally regenerate after spinal cord transection. In response to injury, GFAP+ glial cells in the axolotl spinal cord proliferate and migrate to replace the missing neural tube and create a permissive environment for axon regeneration. Molecular pathways that regulate the pro-regenerative axolotl glial cell response are poorly understood. Here we show axolotl glial cells up-regulate AP-1cFos/JunB after injury, which promotes a pro-regenerative glial cell response. Injury induced upregulation of miR-200a in glial cells supresses c-Jun expression in these cells. Inhibition of miR-200a during regeneration causes defects in axonal regrowth and transcriptomic analysis revealed that miR-200a inhibition leads to differential regulation of genes involved with reactive gliosis, the glial scar, extracellular matrix remodeling and axon guidance. This work identifies a unique role for miR-200a in inhibiting reactive gliosis in axolotl glial cells during spinal cord regeneration.This reseach was supported by a Regenerative Medicine Minnesota Grant and a NIH NCID R01 to KE. KZS has been supported by a NIH T32 GM113846 grant

Surface anisotropy and particle size influence on hysteresis loops in La2/3Ca1/3MnO3 nanoparticles : A simulation approach

Thermal and hysteretic magnetic properties of La2/3Ca1/3MnO3 nanoparticles were studied using Monte Carlo simulations, with emphasis on the influence of anisotropy. In this work, several nanoparticle sizes ranging from 2.32 to 11.58 nm were analyzed and their properties were compared to those of the bulk material. The magnetic behavior of the material was modeled using the three dimensional Heisenberg model with nearest neighbor interactions. Furthermore, both uniaxial and Néel anisotropies were considered for core and surface magnetic sites respectively. Deviations in the critical temperature and coercive field were observed for nanoparticles when compared with those of the bulk material. In addition to these properties, the special spin configurations that arise from the competition between the exchange, anisotropy and external magnetic field were also studied. All these effects are interpreted in terms of the surface properties such as the Néel anisotropy and the decrease in the coordination number

Desenlaces clínicos en nefritis lúpica. Reporte de una serie de casos del Hospital Militar Central de Bogotá

The following retrospective series of cases aims to describe the characteristics and clinical outcomes of patients at the Central Military Hospital of Bogotá with proliferative lupus nephritis. It is frequently found at the time of diagnosis proteinuria, 37% of them in nephrotic range, and alterations in uroanalysis. We describe the results of the main hematological and immunological variables. We did not find differences between the types of induction nor in the outcomes as: percentage of remission, decrease of creatinine and proteinuria reduction.La presente serie retrospectiva de casos, pretende describir las características y desenlaces clínicos de los pacientes del Hospital Militar Central de Bogotá, con nefritis lúpica proliferativa. Es frecuente encontrar al momento del diagnóstico proteinuria, 37% de ellas en rango nefrótico y alteraciones en el uroanálisis.Describimos los resultados de las principales variables hematológicas e inmunológicas. No encontramos diferencias entre los tipos de inducción ni en los desenlaces como: porcentaje de remisión, disminución de creatinina y reducción de proteinuria

Left Spigelian Hernia in Super-Obese Patient: A Case-Report.

Abstract: We report a case in which a giant Spigelian hernia presented with severe, persistent abdominal pain in a 62- year-old super-obese woman with a history of total abdominal hysterectomy-bilateral salpingo-oopherectomy at the age of 40 years for benign neoplasia, who later underwent open hernia repair (maximal diameter of the hernia sac: 21 cm) because of the development of compartment syndrome. Afterward, although a large incarcerated hernia disease was found, the sac removal was technically difficult and an open procedure was carried out, with double-mesh placement. No complications were recorded during the post-operative course. We report a difficult issue related to the diagnosis and management of this pathology, underlining the complete surgical repair to avoid hernia recurrence

Razlike u razinama anti-Müllerovog hormona u krvnoj plazmi i reproduktivnih parametara između dvije vrste goveda Bos indicus i Bubalus bubalis

The aim of this study was to evaluate the possible relationships between reproductive parameters and Anti Mullerian Hormone (AMH) levels in two closely related bovine species. AMH levels and the reproductive parameters of 50 water buffaloes (Bubalus bubalis) and 50 Zebu cattle (Bos indicus) of the same age and raised in similar conditions were evaluated. Clinical data were obtained from the farm in specialized designed format, and AMH was measured by ELISA. The results show that Zebu cattle had higher AMH levels than water buffaloes (P<0.0001), while water buffaloes exhibited better reproductive parameters: days open to pregnancy (P<0.0001), parity (P<0.0005), age at first calving (P<0.0001), and intercalving period (P<0.0001). Although both species have different reproductive parameters, no correlations were found between AMH and the reproductive parameters evaluated in either species. Finally, pregnant Zebu cattle and water buffalo showed a tendency to have lower AMH levels than non-pregnant counterparts. The results are paradoxical as the species with lower AMH levels exhibited better reproductive parameters, suggesting that the reproductive parameters within the herd do not depend solely on the ovarian reserve of females.Cilj je ovog rada bio procijeniti je li moguće ustanoviti povezanost između reproduktivnih parametara i razina anti-Müllerovog hormona (AMH) u dvije blisko srodne vrste goveda. Analizirane su razine AMH i reproduktivni parametri 50 bivola (Bubalus bubalis) i 50 zebu goveda (Bos indicus) iste dobi uzgojenih u sličnim uvjetima. Klinički podatci dobiveni su s farme u posebno osmišljenom pokusu. AMH je određivan pomoću ELISA metode. Rezultati pokazuju da su razine AMH više u goveda nego u bivola (P<0,0001). Bivoli su pokazali bolje reproduktivne parametre: servisno razdoblje (P<0,0001), paritet (P<0,0005), dob kod prvog teljenja (P<0,0001) i međutelidbeno razdoblje (P<0,0001). Premda obje vrste imaju različite reproduktivne parametre, nije ustanovljena povezanost između AMH i analiziranih reproduktivnih parametara niti u jedne od istraživanih vrsta. Zaključno, steone ženke goveda i bivola pokazuju tendenciju manjih razina AMH u usporedbi s nesteonim. Rezultati dobiveni u ovoj studiji su paradoksalni, jer vrste s nižim AMH razinama pokazuju bolje reproduktivne parametre. Ovi rezultati ukazuju na to da reproduktivni parametri unutar krda ne ovise samo o rezervi jajnih stanica u ženki