Gα16 protein expression is up- and down-regulated following T-cell activation: disruption of this regulation impairs activation-induced cell responses

AbstractThe role of heterotrimeric G proteins in T-cell activation is poorly understood. Here we show that in normal, mature human T-cells, expression of Gα16, the 43 kDa α subunit of G16, varies widely, depending on T-cell activation status. Quiescent blood lymphocytes strongly up-regulate Gα16 after Leuco A stimulation: protein expression of Gα16 is maximal at day 4, then decreases. Consistently, in human T-cell clones, expression of Gα16 is high in the first week following activation and decreases rapidly within the second week. In addition, permanent disruption of regulated Gα16 expression in Jurkat T-cells by stable overexpression of 43 kDa Gα16 inhibited Leuco A-induced interleukin-2 production, CD69 up-regulation and cell apoptosis (by 58%, 46% and 74%, respectively), suggesting that coordinate regulation of Gα16 expression is necessary for optimal activation-induced T-cell responses, and that Gα16 proteins may be involved in the negative regulation of TCR signalling

Unquenching the Quark Model and Screened Potentials

The low-lying spectrum of the quark model is shown to be robust under the effects of `unquenching'. In contrast, the use of screened potentials is shown to be of limited use in models of hadrons. Applications to unquenching the lattice Wilson loop potential and to glueball mixing in the adiabatic hybrid spectrum are also presented.Comment: 6 pages, 3 ps figures, revtex. Version to appear in J. Phys.

Mycophenolic Acid overcomes imatinib and nilotinib resistance of chronic myeloid leukemia cells by apoptosis or a senescent-like cell cycle arrest.

International audienceWe used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease

Interprofessional Role of Cadaver Laboratory Experience in Paramedic Education at Creighton University

This brief report introduces and provides a reflection on the interprofessional role of an annual cadaver laboratory experience in the paramedic program at Creighton University, United States. Similar experiences in paramedic education have been noted to be beneficial in increasing paramedic student’s knowledge of anatomy and ability to perform procedures. Learners that participated in this report and reflection reported gains in their education and appreciation of other professions that support previous research on the topic and the value of this distinct experience.

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

Chromosomal translocations involving the EVI1 locus are a recurrent finding in myeloid leukemia and are associated with poor prognosis. In this study, we performed a detailed molecular characterization of the recurrent translocation t(3;17)(q26;q22) in 13 hematologic malignancies. The EVI1 gene locus was rearranged in all 13 patients and was associated with EVI1 overexpression. In 9 out of 13 patients, the 17q breakpoints clustered in a 250 kb region on band 17q22 encompassing the MSI2 (musashi homologue 2) gene. Expression analyses failed to demonstrate ectopic MSI2 expression or the presence of an MSI2/EVI1 fusion gene. In conclusion, we show for the first time that the t(3;17) is indeed a recurrent chromosomal aberration in myeloid malignancies. In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3; 17)

Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea:European observational study

Background: Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%–24% of PV patients report intolerance and resistance to HU. Methods: This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. Results: In the 350 enrolled patients, 70% were &gt;60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit &lt;45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. Conclusion: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.</p

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity

On the Challenges and Opportunities in Generative AI

The field of deep generative modeling has grown rapidly and consistently over the years. With the availability of massive amounts of training data coupled with advances in scalable unsupervised learning paradigms, recent large-scale generative models show tremendous promise in synthesizing high-resolution images and text, as well as structured data such as videos and molecules. However, we argue that current large-scale generative AI models do not sufficiently address several fundamental issues that hinder their widespread adoption across domains. In this work, we aim to identify key unresolved challenges in modern generative AI paradigms that should be tackled to further enhance their capabilities, versatility, and reliability. By identifying these challenges, we aim to provide researchers with valuable insights for exploring fruitful research directions, thereby fostering the development of more robust and accessible generative AI solutions