Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy

The RNA binding protein Human antigen R (HuR) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes. Specifically, HuR cytoplasmic translocation is significantly increased in NRVMs (neonatal rat ventricular myocytes) following treatment with phenylephrine or angiotensin II, agonists of two independent Gαq-coupled GPCRs known to induce hypertrophy. This Gq-mediated HuR activation is dependent on p38 MAP kinase, but not canonical Gq-PKC signaling. Furthermore, we show that HuR activation is necessary for Gq-mediated hypertrophic growth of NRVMs as siRNA-mediated knockdown of HuR inhibits hypertrophy as measured by cell size and expression of ANF (atrial natriuretic factor). Additionally, HuR overexpression is sufficient to induce hypertrophic cell growth. To decipher the downstream mechanisms by which HuR translocation promotes cardiomyocyte hypertrophy, we assessed the role of HuR in the transcriptional activity of NFAT (nuclear factor of activated T cells), the activation of which is a hallmark of cardiac hypertrophy. Using an NFAT-luciferase reporter assay, we show an acute inhibition of NFAT transcriptional activity following pharmacological inhibition of HuR. In conclusion, our results identify HuR as a novel mediator of cardiac hypertrophy downstream of the Gq-p38 MAPK pathway, and suggest modulation of NFAT activity as a potential mechanism

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

14-3-3theta Protects against Neurotoxicity in a Cellular Parkinson's Disease Model through Inhibition of the Apoptotic Factor Bax

Disruption of 14-3-3 function by alpha-synuclein has been implicated in Parkinson's disease. As 14-3-3s are important regulators of cell death pathways, disruption of 14-3-3s could result in the release of pro-apoptotic factors, such as Bax. We have previously shown that overexpression of 14-3-3θ reduces cell loss in response to rotenone and MPP+ in dopaminergic cell culture and reduces cell loss in transgenic C. elegans that overexpress alpha-synuclein. In this study, we investigate the mechanism for 14-3-3θ's neuroprotection against rotenone toxicity. While 14-3-3s can inhibit many pro-apoptotic factors, we demonstrate that inhibition of one factor in particular, Bax, is important to 14-3-3s' protection against rotenone toxicity in dopaminergic cells. We found that 14-3-3θ overexpression reduced Bax activation and downstream signaling events, including cytochrome C release and caspase 3 activation. Pharmacological inhibition or shRNA knockdown of Bax provided protection against rotenone, comparable to 14-3-3θ's neuroprotective effects. A 14-3-3θ mutant incapable of binding Bax failed to protect against rotenone. These data suggest that 14-3-3θ's neuroprotective effects against rotenone are at least partially mediated by Bax inhibition and point to a potential therapeutic role of 14-3-3s in Parkinson's disease

The Core Apoptotic Executioner Proteins CED-3 and CED-4 Promote Initiation of Neuronal Regeneration in Caenorhabditis elegans

Laser severing of individual axons in the nematode Caenorhabditis elegans revealed that the apoptotic executioner caspase CED-3 and its regulator CED-4/Apaf-1 play an unexpected beneficial role in promoting axonal regeneration

PaLM 2 Technical Report

We introduce PaLM 2, a new state-of-the-art language model that has better multilingual and reasoning capabilities and is more compute-efficient than its predecessor PaLM. PaLM 2 is a Transformer-based model trained using a mixture of objectives. Through extensive evaluations on English and multilingual language, and reasoning tasks, we demonstrate that PaLM 2 has significantly improved quality on downstream tasks across different model sizes, while simultaneously exhibiting faster and more efficient inference compared to PaLM. This improved efficiency enables broader deployment while also allowing the model to respond faster, for a more natural pace of interaction. PaLM 2 demonstrates robust reasoning capabilities exemplified by large improvements over PaLM on BIG-Bench and other reasoning tasks. PaLM 2 exhibits stable performance on a suite of responsible AI evaluations, and enables inference-time control over toxicity without additional overhead or impact on other capabilities. Overall, PaLM 2 achieves state-of-the-art performance across a diverse set of tasks and capabilities. When discussing the PaLM 2 family, it is important to distinguish between pre-trained models (of various sizes), fine-tuned variants of these models, and the user-facing products that use these models. In particular, user-facing products typically include additional pre- and post-processing steps. Additionally, the underlying models may evolve over time. Therefore, one should not expect the performance of user-facing products to exactly match the results reported in this report

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Relapsed Acute Lymphoblastic Leukemia Presenting as Acute Renal Failure

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. It is an aggressive hematologic neoplasm, with a bimodal age distribution typically presenting in childhood and the decade of life (Terwilliger and Abdul-Hay, 2017). Renal injury in ALL is common and can occur through many different mechanisms, such as prerenal acute kidney injury, acute tubular necrosis, renovascular disease, obstruction, glomerulonephritis, and parenchymal infiltration of tumor cells (Luciano and Brewster, 2014). Infiltration of kidneys by leukemia cells is common; however a resultant injury only occurs in about 1% of patients, and renal failure is even more rare (Luciano and Brewster, 2014). Renal failure due to bilateral infiltration of tumor cells has been reported in only a few cases and is thought to be a poor prognostic indicator (Luciano and Brewster, 2014; Sherief et al., 2015). Biopsy is essential to the diagnosis of renal infiltration of leukemia. We present a case of acute renal failure secondary to bilateral renal infiltration of ALL presenting as the first sign of relapse in a young man

Relapsed Acute Lymphoblastic Leukemia Presenting as Acute Renal Failure

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. It is an aggressive hematologic neoplasm, with a bimodal age distribution typically presenting in childhood and the 6th decade of life (Terwilliger and Abdul-Hay, 2017). Renal injury in ALL is common and can occur through many different mechanisms, such as prerenal acute kidney injury, acute tubular necrosis, renovascular disease, obstruction, glomerulonephritis, and parenchymal infiltration of tumor cells (Luciano and Brewster, 2014). Infiltration of kidneys by leukemia cells is common; however a resultant injury only occurs in about 1% of patients, and renal failure is even more rare (Luciano and Brewster, 2014). Renal failure due to bilateral infiltration of tumor cells has been reported in only a few cases and is thought to be a poor prognostic indicator (Luciano and Brewster, 2014; Sherief et al., 2015). Biopsy is essential to the diagnosis of renal infiltration of leukemia. We present a case of acute renal failure secondary to bilateral renal infiltration of ALL presenting as the first sign of relapse in a young man

Relapsed Acute Lymphoblastic Leukemia Presenting as Acute Renal Failure

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. It is an aggressive hematologic neoplasm, with a bimodal age distribution typically presenting in childhood and the decade of life (Terwilliger and Abdul-Hay, 2017). Renal injury in ALL is common and can occur through many different mechanisms, such as prerenal acute kidney injury, acute tubular necrosis, renovascular disease, obstruction, glomerulonephritis, and parenchymal infiltration of tumor cells (Luciano and Brewster, 2014). Infiltration of kidneys by leukemia cells is common; however a resultant injury only occurs in about 1% of patients, and renal failure is even more rare (Luciano and Brewster, 2014). Renal failure due to bilateral infiltration of tumor cells has been reported in only a few cases and is thought to be a poor prognostic indicator (Luciano and Brewster, 2014; Sherief et al., 2015). Biopsy is essential to the diagnosis of renal infiltration of leukemia. We present a case of acute renal failure secondary to bilateral renal infiltration of ALL presenting as the first sign of relapse in a young man