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Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P 2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38–GSK3β–β-catenin and WNT5A–LRP5 pathways. Accordingly, S1P 2 -deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases. Promoting more bone growth is of keen interest in the treatment of osteoporosis, and preventing the degradation of S1P offers a new therapeutic avenue for this approach.

In recent years it has become more and more apparent that the regulation of gene expression by RNA-binding proteins (RBPs) is of utmost importance for most cellular signaling pathways. RBPs control several aspects of RNA biogenesis including splicing, localization, stability, and translation efficiency. One of these RBPs is RBM47 that recently has been suggested to function as a tumor suppressor as it was shown to suppress breast and colon cancer progression. Here we demonstrate that RBM47 is an important regulator of basal and DNA damage-induced p53 and p21WAF1/CIP1 protein expression. Knockdown of RBM47 by siRNAs results in a strong reduction in p53 mRNA and protein levels due to an impaired p53 promoter activity. Accordingly, overexpression of Flag-RBM47 enhances p53 promoter activity demonstrating that RBM47 regulates p53 at the transcriptional level. By controlling p53, knockdown of RBM47 concomitantly decreases also p21 expression at the transcriptional level, driving irradiated carcinoma cell lines from different entities into cell death rather than into senescence. Thus, RBM47 represents a novel molecular switch of cell fate decisions that functions as a regulator of the p53/p21-signaling axis.

Background Plants have evolved alongside microbes, enabling plants to better cope with abiotic and biotic stress. Interactions between plant roots and local soil microbes are critical for environmental adaptation and plant health. Plants actively regulate the microbial community composition in their rhizospheres to recruit specific microorganisms that enhance their fitness in the ecosystem they inhabit. This study builds on prior research suggesting that plants exhibit a “home field advantage” by preferentially recruiting microbes unique to their native environments, likely through mutual recognition and selective recruitment mechanisms. Results Using gene- and genome-centric approaches, we assess the functional potential of root-associated microbes and profile their host metabolites to uncover the metabolic outputs potentially regulating host‒microbe interactions in Andropogon gerardii . We find that plants adapted to drier environments experience less stress, producing fewer stress-related metabolites and impacting the recruitment of microbes with genes linked to stress relief pathways. In particular, plant-derived trimethyllysine is highly associated with microbial populations capable of improving nutrient uptake, producing plant growth-promoting compounds, and modulating stress responses. Conclusions This study highlights the critical interplay between host exudates and microbial substrate uptake as the primary mechanism of rhizosphere assembly. We demonstrate that plants actively produce metabolites to recruit microbial populations with the functional potential to enhance their ability to thrive in stressful environments. This research provides insights into the mechanisms of plant–microbe communication, rhizosphere recruitment, and the complex interplay of plant–microbe interactions. Furthermore, it highlights promising avenues for manipulating rhizosphere microbiomes to support conservation agriculture when coping with climate change.

Wild weather and tornadoes across the country as 35 million people in the U.S. are facing the threat of severe storms today. A tragedy in Mississippi as two police officers one a rookie, the other officer of the year, are gunned down and killed during a traffic stop in Hattiesburg, Mississippi. Now, three suspects are currently in custody after a massive manhunt overnight. A historic meeting between the president of Cuba and Pope at the Vatican today. Candid words from Michelle Obama on the emotional toll being a black first lady. Renewed concerns today over how safe the U.S. is from home grown terrorism, some startling comments about the terror threat in this country with one security expert saying just this weekend that the threat now is bigger than it was following 9/11.

Thousands of people remain under weather warnings and watches. In Houston, an apartment building collapsed around 6:30 this morning after apparently being hit by a tornado. Two people were sent to the hospital, but there were no serious injuries. The 86-year-old John Nash and his wife Alicia were riding in a taxi in New Jersey when the wreck occurred. The mayor and police chief are praising protesters for relatively peaceful demonstrations following the acquittal of Officer Michael Brelo in the shooting deaths of two unarmed people. Lebron James is calling on the protesters to bring their excitement and that passion on display last night to support the Cavaliers. California prosecutors investigate what caused Tuesday's massive oil spill in Santa Barbara County, the environmentalists are working tirelessly to rescue sea lions and pelicans caught in the toxic tar. Nine officers in total claiming the African-American officers involved in the case were treated less harshly and that it is not the first time that's happened. The report says that GM is negotiating what could be a record settle with the government. CBS reporter Kimberly Dozier and her crew, along with a member -- and members of the U.S. army patrol were out filming a story, but what started out as so many other days had begun in the war-torn city turned into an absolute nightmare.

Militants attacked an Iraqi military post in Anbar Province and walked away with, dozens of weapons, M-16s, heavy machine guns, and also American armored vehicles, Humvees. They left behind a trail of death, the burned bodies of Iraqi soldiers. Closing arguments could begin as early as Monday in the American sniper trial; both the prosecution and the defense are relying on key expert witnesses to prove their cases. Sources say that Bobbi Kristina Brown has had her breathing tube removed; the daughter of the late Whitney Houston and singer Bobby Brown is now ventilated through a hole in her throat. Former New York Mayor Rudy Giuliani is again standing by his comments questioning the love President Obama has for the United States. Former New York Mayor Rudy Giuliani is again standing by his comments questioning the love President Obama has for the United States.

American-made weapons are falling into the hands of ISIS fighters in Iraq, the militants apparently attacked an Iraqi military post in Anbar Province; they seized dozens of weapons, M-16s and heavy machine guns and even armored vehicles. A manhunt is under way after a police officer was ambushed and then shot while sitting in his patrol car. The man accused of gunning down a Las Vegas mother in a so-called road rage incident reportedly bragged about the shooting; his friends telling police he said, quote, \"They were after me and I got them,\" end quote. A stunning new intelligence report from the Department of Homeland Security showing that threat of homegrown terror is growing; the report focuses on the threat from the so-called right wing Sovereign Citizens Movement. Former Mayor Rudy Giuliani doubling down on remarks he made about President Obama's patriotism, this week, Giuliani objected to the president's refusal to label the terror problem an Islamic extremist issue and says President Obama doesn't love America.

Countries across Europe are on edge. Authorities are guarding against potential terror attacks there. One intelligence source tells CNN, dozens of terrorists may be poised to strike across Europe as part of the so-called sleeper cells in Belgium, troops are out in force, guarding targets, including embassies and the country's Jewish museum. Hours ago, the Yemeni president's chief of staff was kidnapped by gunmen in Central Sanaa in broad daylight. So in the wake of the Paris attacks, U.S. Attorney General Eric Holder warned of similar potential attacks in the U.S. The man arrested last week for allegedly plotting to bomb and open fire on the U.S. capitol will remain behind bars. NASCAR driver, Kurt Busch, claims ex-girlfriend is a trained assassin.