SPAIN'S 24-hour death toll from coronavirus has hit one of the lowest levels since March 18.

Efforts to stop the spread of COVID-19 translate into a financial challenge for nearly everyone connected to the production of live music.

This year, I am currently making over $12,000 less a year then I was supposed to when I was hired in 2004, a letter to the editor says.

We have not kept up, and we are losing a generation of teachers.

Our state is taking the wise step of reducing unnecessary public gatherings and that includes voting.

The Butler Bulldogs are coming off an NIT season as LaVall Jordan enters his third year as coach

Kurt Koehler, founder and president of AlGalCo, shows his HOT (Hydrogen on Tap) system.

The IndyCar schedule has undergone another massive change, but this time, the series has managed to add a race back onto the slate.

IndyCar Series action is now set to begin in June at Texas; there are two doubleheaders on tap and another race at Indianapolis Motor Speedway

A big change in Indianapolis' education landscape is a reminder of how much things have improved in recent years.

Matt Tully was dedicated to his craft and to this community. The Matthew L. Tully Memorial Fund is a meaningful way to keep his memory and work alive.

From federal funds to decisions about opening and closing schools, here's how census data makes a difference for schools.

Indianapolis Colts will play their AFC South foes twice each, and also the Baltimore Ravens and Green Bay Packers

The Indianapolis Colts play every team from the AFC North and AFC North, as well as each AFC South foe twice, the New York Jets and Las Vegas Raiders.

The Indianapolis Colts start and finish the 2020 season against the Jacksonville Jaguars; the Colts are on the road to start the year and at home to finish it.

The only time Indianapolis will be in prime time will be a Thursday night showdown with the rival Tennessee Titans. At their place in Nashville.

Hoosiers are scheduled to start the season against Wisconsin and finish with the traditional Old Oaken Bucket game.

Indiana Pacers are coming off a second straight season with 48 regular-season wins and a first-round playoff loss

Purdue men's basketball is coming off of an Elite Eight season as Matt Painter enters his 15th season as coach

Some people like to read something more unusual than magazines or books. Take Away English reports.

Indiana Pacers are coming off a second straight season with 48 regular-season wins and a first-round playoff loss

"When you think about people that pay it forward, he really captured the essence of someone that consistently did that on a daily basis."

Indianapolis Colts will play their AFC South foes twice each, and also the Baltimore Ravens and Green Bay Packers

The Indianapolis Colts play every team from the AFC North and AFC North, as well as each AFC South foe twice, the New York Jets and Las Vegas Raiders.

The only time Indianapolis will be in prime time will be a Thursday night showdown with the rival Tennessee Titans. At their place in Nashville.

The Indianapolis Colts start and finish the 2020 season against the Jacksonville Jaguars; the Colts are on the road to start the year and at home to finish it.

Indiana educators are among the strongest advocates for students and deserve the utmost appreciation and respect, Jennifer McCormick writes.

Higher education is prepared to play its part in a recovery that accelerates a stronger economy and personal opportunity, Teresa Lubbers writes.

Science instruments sense a big dip in seismic noise as the population stays at home.

Women have long felt the pressure of looking the part. Now men are feeling it, too.

Milwaukee has embraced the modern NBA.

The Ravens' Ty Montgomery figures to take on a larger share of the workload in Baltimore over the remainder of the season.

The rapper said she wanted to support women's and LGTBQ rights.

Establishing daily and weekly routines provides a structure for learning at home. Parents and children know how the day will unfold; routines create predictability and also anticipation for the fun and comforting things that will happen throughout the day. It can be helpful to identify a learning theme to explore together over the course of two weeks. You'll find a sample daily schedule below, with ideas for how to bring in the theme into every part of the day, from breakfast to read alouds to art and science activities. 

REALTORS® Urge Deduction for Rental Income

Phishing is incredibly common, yet most people feel it has gotten harder to spot in recent years. Cyber criminals rely on their knowledge of human psychology to make you do things you wouldn’t normally do. They also know that if they scare you enough they can manipulate you into doing what they want you to […]

The post Preventing Phishing With Education appeared first on Dumb Little Man.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression.

N. Leigh Anderson
Apr 1, 2004; 3:311-326
Research

Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity.

Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity.

MS Brown
Jul 1, 1980; 21:505-517
Reviews

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles

W Gamble
Nov 1, 1978; 19:1068-1070
Articles

23 April 2020

pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression.

Michael Trick talks about creating schedules for leagues.

New Publication: Rules, Procedures and Mechanisms Applicable to Processes under the Cartagena Protocol on Biosafety.