Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1^fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1^fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1^fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

Porphyromonas gingivalis is a Gram-negative anaerobic periodontal microorganism strongly associated with tissue-destructive processes in human periodontitis. Following oral infection with P. gingivalis, the periodontal bone loss in mice is reported to require the engagement of Toll-like receptor 2 (TLR2). Serine-glycine lipodipeptide or glycine aminolipid classes of P. gingivalis engage human and mouse TLR2, but a novel lipid class reported here is considerably more potent in engaging TLR2 and the heterodimer receptor TLR2/TLR6. The novel lipid class, termed Lipid 1256, consists of a diacylated phosphoglycerol moiety linked to a serine-glycine lipodipeptide previously termed Lipid 654. Lipid 1256 is approximately 50-fold more potent in engaging TLR2 than the previously reported serine-glycine lipid classes. Lipid 1256 also stimulates cytokine secretory responses from peripheral blood monocytes and is recovered in selected oral and intestinal Bacteroidetes organisms. Therefore, these findings suggest that Lipid 1256 may be a microbial TLR2 ligand relevant to chronic periodontitis in humans.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

The adipocyte-derived hormone leptin increases trafficking of KATP and Kv2.1 channels to the pancreatic β-cell surface, resulting in membrane hyperpolarization and suppression of insulin secretion. We have previously shown that this effect of leptin is mediated by the NMDA subtype of glutamate receptors (NMDARs). It does so by potentiating NMDAR activity, thus enhancing Ca2+ influx and the ensuing downstream signaling events that drive channel trafficking to the cell surface. However, the molecular mechanism by which leptin potentiates NMDARs in β-cells remains unknown. Here, we report that leptin augments NMDAR function via Src kinase–mediated phosphorylation of the GluN2A subunit. Leptin-induced membrane hyperpolarization diminished upon pharmacological inhibition of GluN2A but not GluN2B, indicating involvement of GluN2A-containing NMDARs. GluN2A harbors tyrosine residues that, when phosphorylated by Src family kinases, potentiate NMDAR activity. We found that leptin increases phosphorylation of Tyr-418 in Src, an indicator of kinase activation. Pharmacological inhibition of Src or overexpression of a kinase-dead Src mutant prevented the effect of leptin, whereas a Src kinase activator peptide mimicked it. Using mutant GluN2A overexpression, we show that Tyr-1292 and Tyr-1387 but not Tyr-1325 are responsible for the effect of leptin. Importantly, β-cells from db/db mice, a type 2 diabetes mouse model lacking functional leptin receptors, or from obese diabetic human donors failed to respond to leptin but hyperpolarized in response to NMDA. Our study reveals a signaling pathway wherein leptin modulates NMDARs via Src to regulate β-cell excitability and suggests NMDARs as a potential target to overcome leptin resistance.

Communication between individuals via molecules, termed chemosignaling, is widespread among animal and plant species. However, we lack knowledge on the specific functions of the substances involved for most systems. The femoral gland is an organ that secretes a waxy substance involved in chemical communication in lizards. Although the lipids and volatile substances secreted by the femoral glands have been investigated in several biochemical studies, the protein composition and functions of secretions remain completely unknown. Applying a proteomic approach, we provide the first attempt to comprehensively characterize the protein composition of femoral gland secretions from the Galápagos marine iguana. Using samples from several organs, the marine iguana proteome was assembled by next-generation sequencing and MS, resulting in 7513 proteins. Of these, 4305 proteins were present in the femoral gland, including keratins, small serum proteins, and fatty acid-binding proteins. Surprisingly, no proteins with discernible roles in partner recognition or inter-species communication could be identified. However, we did find several proteins with direct associations to the innate immune system, including lysozyme C, antileukoproteinase (ALP), pulmonary surfactant protein (SFTPD), and galectin (LGALS1) suggesting that the femoral glands function as an important barrier to infection. Furthermore, we report several novel anti-microbial peptides from the femoral glands that show similar action against Escherichia coli and Bacillus subtilis such as oncocin, a peptide known for its effectiveness against Gram-negative pathogens. This proteomics data set is a valuable resource for future functional protein analysis and demonstrates that femoral gland secretions also perform functions of the innate immune system.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.

Trypsin is the protease of choice in bottom-up proteomics. However, its application can be limited by the amino acid composition of target proteins and the pH of the digestion solution. In this study we characterize ProAlanase, a protease from the fungus Aspergillus niger that cleaves primarily on the C-terminal side of proline and alanine residues. ProAlanase achieves high proteolytic activity and specificity when digestion is carried out at acidic pH (1.5) for relatively short (2 h) time periods. To elucidate the potential of ProAlanase in proteomics applications, we conducted a series of investigations comprising comparative multi-enzymatic profiling of a human cell line proteome, histone PTM analysis, ancient bone protein identification, phosphosite mapping and de novo sequencing of a proline-rich protein and disulfide bond mapping in mAb. The results demonstrate that ProAlanase is highly suitable for proteomics analysis of the arginine- and lysine-rich histones, enabling high sequence coverage of multiple histone family members. It also facilitates an efficient digestion of bone collagen thanks to the cleavage at the C terminus of hydroxyproline which is highly prevalent in collagen. This allows to identify complementary proteins in ProAlanase- and trypsin-digested ancient bone samples, as well as to increase sequence coverage of noncollagenous proteins. Moreover, digestion with ProAlanase improves protein sequence coverage and phosphosite localization for the proline-rich protein Notch3 intracellular domain (N3ICD). Furthermore, we achieve a nearly complete coverage of N3ICD protein by de novo sequencing using the combination of ProAlanase and tryptic peptides. Finally, we demonstrate that ProAlanase is efficient in disulfide bond mapping, showing high coverage of disulfide-containing regions in a nonreduced mAb.

Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

IBM and NASA have developed a new AI foundation model for a wide range of climate and weather applications, with contributions from the Department of Energy’s Oak Ridge National Laboratory. […]

The post IBM and NASA Launch Open-Source AI Model for Advanced Climate and Weather Research appeared first on HPCwire.

The Mediterranean island nation of Cyprus signed the U.S.-led Artemis Accords on Wednesday, becoming the 46th signatory to the agreement that establishes principles for the safe exploration of space.

The four-member SpaceX Crew-8 aboard Crew Dragon Endeavour returned to Earth early Friday, completing their nearly eight-month mission in space.

NASA has identified nine possible landing sites for its Artemis III mission in September 2026 that will return astronauts to the moon for the first time in more than 50 years, the space agency announced Monday.

NASA said on Tuesday that it will restart its Mentor-Protégé Program for contractors on Friday to expand commercial markets with eligible small businesses.

NASA is inviting pubic participation in some virtual activities to watch the SpaceX space station resupply mission scheduled for a Monday night liftoff from NASA's Kennedy Space Center in Florida.

NASA engineers fired the engines on the X-59 research aircraft in advance of planned test flights to determine if the aircraft can reduce sonic booms and make supersonic flight over land quieter.

The three NASA astronauts that were part of the SpaceX Crew-8 aboard Crew Dragon Endeavour will speak publicly today for the first time since their mission returned to earth late last month.

A new technology developed by NASA to predict space weather showed that Hurricane Helene produced "enormous" waves in the Earth's upper atmosphere as it came ashore on Sept. 26, the agency says.

Mary Jackson's story is among those depicted in the book "Hidden Figures," which focused on the lives of black women who worked as mathematicians and engineers for NASA during the Space Race. Before landing there, Jackson worked as a math teacher in Maryland.

Robbert Havekes
Dec 12, 2012; 32:18137-18149
BehavioralSystemsCognitive

Shiaoching Gong
Sep 12, 2007; 27:9817-9823
Toolbox

Experts are working on a unique experiment that will use an inflatable aeroshell/heat shield to protect a spacecraft when entering a planet's atmosphere or returning to Earth

The space suits used by the astronauts on Gemini 7, known as grasshopper suits, were designed for comfort. But after two weeks inside them, that was the last thing on the crew’s minds.

In 1967, a horrific fire broke out during a routine pre-launch test for the Apollo 1 mission at Cape Kennedy, Florida. It would claim the lives of three NASA astronauts

As part of Project Mercury, NASA prepared to send a chimpanzee, Ham, into space to test the effects of space on a living creature.

Capturing a piece of an asteroid and bringing it to Earth is even more difficult than it is time-consuming. After four years in space, NASA’s OSIRIS-REx craft made a brief landing on the asteroid Bennu to collect samples of the ancient rock. Six months later, part of the spacecraft began its journey home to Earth, and earlier this fall, that sample collection canister landed, via parachute, in Utah. Scientists will be studying those samples of Bennu for decades in the hope of unlocking the mystery of how life on Earth began — but they’ve already learned enough to get them excited. In this episode, we speak with Linda Shiner, the former editor of Air & Space / Smithsonian magazine, about the challenges and triumphs of the OSIRIS-REx mission, and what scientists hope it will teach us about how life on Earth began. Find prior episodes of our show here (https://www.smithsonianmag.com/podcast/) . There’s More to That is a production of Smithsonian magazine and PRX Productions. From the magazine, our team is Chris Klimek, Debra Rosenberg and Brian Wolly. From PRX, our team is Jessica Miller, Adriana Rosas Rivera, Genevieve Sponsler, Terence Bernardo, and Edwin Ochoa. The Executive Producer of PRX Productions is Jocelyn Gonzales. Fact-checking by Stephanie Abramson. Episode artwork by Emily Lankiewicz. Music by APM Music.

A new exhibition at the Smithsonian's National Museum of Natural History combines satellite observations and historical data to offer a "larger-than-life look" at our planet's climate today

The banana duct-taped to a wall was created to be a "reflection on what we value." An upcoming auction may deliver an answer

The farthest spacecraft in the universe went momentarily rogue, but scientists breathed a sigh of relief when it reconnected at an unexpected radio frequency

On its 66th flyby of the king of planets, Juno has captured spectacular views of the stormy atmosphere, processed by citizen scientists

In summer months above the North and South Poles, glowing clouds occasionally form naturally at sunset under the right conditions

CRISPR–Cas9 has revolutionized gene editing for traditional and nontraditional model organisms alike. This tool has opened the door to new mechanistic studies of basic mosquito biology as well as the development of novel vector control strategies based on CRISPR–Cas9, including gene drives that spread genetic elements in the population. Although the promise of the specificity, flexibility, and ease of deployment CRISPR is real, its implementation still requires empirical optimization for each new species of interest, as well as to each genomic target within a given species. Here, we provide an overview of designing and testing single-guide RNAs for the use of CRISPR-based gene editing tools.

SolidWorks software helps cut Crenshaw's new product development time and costs in half

Product, company, and customers earn additional recognition

Africa Trek Coordinator Eduard* reflects on God's gifts: his life, his wife and 13 participants sharing the Gospel with Topnaar and Himba peoples in Namibia.

USA Gymnastics, which develops the U.S. Olympic team, reportedly failed to inform authorities of numerous allegations regarding sexual abuse by coaches.

David Radice, associate professor of physics and of astronomy and astrophysics, has been selected to receive a Sustainment Award from NASA to advance an open-source code called AthenaK for computational astrophysicists. The grant will provide nearly $920,000 over three years.

As 1 million people head to cast ballots, the election results are likely to be announced on Monday.

A team from Penn State Harrisburg spent a week at a NASA facility over the summer, building a scientific experiment and sending it to space through the RockOn! program.

This week, SA Money Report journeys in the heart of war, and comes back with a tale about Naspers' exposure in Russia, and its ties to VKontakte, whose 38-year-old CEO Vladimir Kiriyenko was sanctioned by the US.

Jack Kaye, associate director for research at NASA, is the speaker for the Department of Meteorology and Atmospheric Science’s colloquium scheduled for 3:30 p.m. on Wednesday, Nov. 13, in 112 Walker Building on the University Park campus. He will give the talk “Integration of Vantage Points, Programs, and Approaches for Space-Based Earth Remote Sensing.”

NASA’s Power to Explore Challenge calls on U.S. students to submit ideas for moon missions powered by radioisotope systems. The contest encourages kindergarten through Year 12 students to envision a mission, detail objectives, and apply their unique “power” to achieve mission success. Entries are due by January 31, 2025, and grand prize winners will tour NASA’s Glenn Research Center, gaining insight into the technology and science of space exploration.

NASA’s Chandra X-ray Observatory has unveiled mysterious "knots" in the jet of a supermassive black hole in Centaurus A, a nearby galaxy. These bright, fast-moving features exhibit a higher speed in X-rays than in radio wavelengths, hinting at unexplored physics in black hole jets. Despite financial uncertainties surrounding Chandra's operations, scientists continue to uncover new phenomena in deep space, underscoring the telescope’s enduring value to astrophysics.

The NISAR satellite, a joint NASA-ISRO Earth observation mission launching in 2025, will provide precise data on shifts in Earth’s surface, focusing on high-risk areas. Using advanced radar technology, the satellite aims to support natural disaster response and infrastructure monitoring by tracking subtle movements in regions prone to earthquakes and landslides. With each organisation contributing specialised radar systems, the collaboration is a significant leap forward in space-based Earth monitoring.

NASA's Roman Space Telescope has successfully integrated the Roman Coronagraph, a vital step in detecting planets far beyond our solar system. This tool will help block starlight, enabling the telescope to capture faint planetary light. The coronagraph marks a significant advancement in exoplanet detection, allowing the telescope to observe planets 100 million times fainter than their stars. The mission will provide insights into dark energy, exoplanets, and more, paving the way for future observatories like the Habitable Worlds Observatory.

On September 26, NASA’s Atmospheric Waves Experiment (AWE) captured atmospheric gravity waves caused by Hurricane Helene’s powerful landfall along Florida’s Gulf Coast. These waves, observed as concentric ripples extending from Florida, highlight NASA’s efforts to understand how terrestrial weather can impact space weather and disrupt communication systems. AWE’s observations offer a critical step in decoding the effects of severe storms on the upper atmosphere.

NASA’s Juno probe captured vibrant, high-contrast images of Jupiter’s stormy atmosphere and an up-close view of its moon, Amalthea, during the spacecraft’s 66th flyby on October 23. The images were processed by citizen scientists, enhancing the colours to showcase Jupiter’s unique cloud formations and highlighting details of Amalthea against the backdrop of space. Launched in 2016, Juno’s mission is set to conclude in 2025 with a final dive into Jupiter’s atmosphere.

Nick Jonas even grooved a bit with his mother-in-law, Madhu Chopra at Priyanka Chopra’s cousin’s wedding

Releasing on November 29, Sikandar Ka Muqaddar marks the fourth collaboration between director Neeraj Pandey and Jimmy Shergill

"The script is ready, and I will start shooting from February-March. I was traveling from Dubai to Delhi, and I realized I had left the Masoom 2 script on the plane seat," said Shekhar Kapur