Ecology of Argali in Ikh Nartiin Chuluu, Dornogobi Aymag

Argali sheep (Ovis ammon) are listed as threatened in both Mongolia and internationally. Yet, little is known about the biology and ecology of this species. Available data suggests that Argali in Mongolia are declining due to direct poaching and competition with domestic livestock. We initiated several research projects to better understand and conserve the species. In this report we discuss Argali ecology using radio telemetry. We captured and radio-collared 36 Argali using drive-nets, lamb captures, and dating from 2000–2004. Fifteen collared animals have died: 2 due to capture techniques, 8 from predation, 1 from starvation and exposure, 1 from disease, 1 due to maternal neglect, and 2 of unknown causes. In addition, 1 collar ceased working and 4 others dropped off prematurely. We have collected more than 1,040 locations through mid-May 2004. The majority of the Argali were captured in the northern portion of Ikh Nart. Animals have primarily restricted their movements to that area and have not exhibited seasonal movement patterns. Mean home range size for 17 animals with sufficient data (\u3e 45 days with locations) was 57±3.7 km2 (range = 30– 80 km2) using the 100% minimum convex polygon method, with areas of predicted occurrence of 76±5.3km2 for 95% kernel, 32±3.7 km2 for 75% kernel, 11±1.6 km2 for 50% kernel, and 3.8±0.5 km2 for 25% home ranges. Predation was the main cause (72.7%) of mortality in the collared animals for which cause of death could be determined (non-study related)

Redox-dependent dimerization of p38 alpha mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3

The kinase p38α MAPK (p38α) plays a pivotal role in many biological processes. p38α is activated by canonical upstream kinases that phosphorylate the activation region. The purpose of our study was to determine whether such activation may depend on redox-sensing cysteines within p38α. p38α was activated and formed a disulfide-bound heterodimer with MAP2K3 (MKK3) in rat cardiomyocytes and isolated hearts exposed to H2O2 This disulfide heterodimer was sensitive to reduction by mercaptoethanol and was enhanced by the thioredoxin-reductase inhibitor auranofin. We predicted that Cys-119 or Cys-162 of p38α, close to the known MKK3 docking domain, were relevant for these redox characteristics. The C119S mutation decreased whereas the C162S mutation increased the dimer formation, suggesting that these two Cys residues act as vicinal thiols, consistent with C119S/C162S being incapable of sensing H2O2 Similarly, disulfide heterodimer formation was abolished in H9C2 cells expressing both MKK3 and p38α C119S/C162S and subjected to simulated ischemia and reperfusion. However, the p38α C119S/C162S mutants did not exhibit appreciable alteration in activating dual phosphorylation. In contrast, the anti-inflammatory agent 10-nitro-oleic acid (NO2-OA), a component of the Mediterranean diet, reduced p38α activation and covalently modified Cys-119/Cys-162, probably obstructing MKK3 access. Moreover, NO2-OA reduced the dephosphorylation of p38α by hematopoietic tyrosine phosphatase (HePTP). Furthermore, steric obstruction of Cys-119/Cys-162 by NO2-OA pretreatment in Langendorff-perfused murine hearts prevented the p38-MKK3 disulfide dimer formation and attenuated H2O2-induced contractile dysfunction. Our findings suggest that cysteine residues within p38α act as redox sensors that can dynamically regulate the association between p38 and MKK3.</p

Introduction of GI Wellness Committee to reduce GI fellow burnout and improve wellness.

Gastroenterology (GI) fellowship is an arduous process which predisposes fellows to fatigue and burnout. Our baseline survey showed a large number of our fellows to be in danger of burnout. Aims for Improvement To improve the overall wellness of GI fellows, identify stressors and reduce incidence of burnout. The goal for the first 6 months of operation is to demonstrate improvement in Mini ReZ survey scores by 25% at starting from Sept 1st, 2020

Acute Systemic Infection-Associated Russell Body Gastroesophagitis: A Case Report and Literature Review

Russell body esophagitis/gastritis (RBG) is a rare gastrointestinal inflammatory condition characterized by accumulation of plasma cells containing dense eosinophilic cytoplasmic inclusions, i.e., Russell bodies. Herein, we report a case of RBG in a patient with a systemic inflammation background. A 61-year-old female presented with oral infection. Upper gastrointestinal endoscopy revealed patchy salmon-colored esophageal mucosa proximally to the gastroesophageal junction, suggestive of “Barrett’s esophagus”. Histologic examination of the biopsy tissue from the lower esophagus showed diffuse lymphoplasmacytic infiltration with abundant admixed enlarged plasma cells (Mott cells) containing bright eosinophilic, round, dense, homogenous inclusions (Russell bodies) in cytoplasm. Immunohistochemical study demonstrated membranous staining of CD138 in the Mott cells, while immunoglobulin light chain in situ hybridization revealed positivity of only kappa light chain, indicating kappa light chain restriction and clonality. A proton-pump inhibitor therapy was initiated, but the patient passed away due to generalized infection. Our case suggests that Russell body esophagitis/gastritis (RBG) can be a gastrointestinal presentation associated with acute systemic infection

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Exploiting tumour addiction with a serine and glycine-free diet.

Understanding cancer metabolism is key to unveil the Achilles’ heel of cancer cells and provide novel therapeutic interventions for patients. While the rerouting of metabolic pathways during development1 or cancer transformation and progression2, 3, 4 has been extensively characterised, the exact dynamic of these events, their distribution and frequency in the different tumour types, and the correlation with genetic background remain largely unknown. In a recent article published in Nature, Karen Vousden’s team assesses the effect of serine and glycine dietary restriction in autochthonous mouse tumour models driven by different oncogenes (Maddocks et al, 2017)5, leading to potential area of therapeutic intervention

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with &#60;5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC