Analysis of tree rings shows that two faults near Seattle, Washington ruptured at the same time or soon after each other more than 1000 years ago – a repeat today would cause a major disaster in the region

The Kikai-Akahoya eruption of an underwater volcano off the coast of Japan ejected enough material to fill Lake Tahoe twice, three times as much as the eruption of Mount Tambora in 1815

Scientists used AI to transform tourist photos into a 3D digital map of Antarctic penguin colonies – even as researchers debate whether to harness or discourage tourism in this remote region

The Impossible Man by Patchen Barss salutes Roger Penrose's groundbreaking work in physics and mathematics while challenging the idea that a genius should be exempt from ordinary obligations

Wooden tablets containing a language of glyphs called Rongorongo may be evidence that the people of Rapa Nui, also known as Easter Island, created their own writing system without the influence of European language

Historians have claimed the people of Easter Island overexploited natural resources, causing a population crash, but new evidence suggests they lived sustainably for centuries

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Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.

Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.

Memory formation is contingent on molecular and structural changes in neurons in response to learning stimuli—a process known as neuronal plasticity. The initiation step of mRNA translation is a gatekeeper of long-term memory by controlling the production of plasticity-related proteins in the brain. The mechanistic target of rapamycin complex 1 (mTORC1) controls mRNA translation, mainly through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). mTORC1 signaling decreases throughout brain development, starting from the early postnatal period. Here, we discovered that in mice, the age-dependent decrease in mTORC1 signaling occurs selectively in excitatory but not inhibitory neurons. Using a gene conditional knockout (cKO) strategy, we demonstrate that either up- or downregulating the mTORC1-4E-BP2 axis in GAD65 inhibitory interneurons, but not excitatory neurons, results in long-term object recognition and object location memory deficits. Our data indicate that the mTORC1 pathway in inhibitory but not excitatory neurons plays a key role in memory formation.

Vault RNAs (vtRNAs) are evolutionarily conserved small noncoding RNAs transcribed by RNA polymerase III. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions, including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as a noncanonical source of miRNAs, which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles, including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss-of-function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts, pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment.

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca²⁺ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca²⁺ currents were inhibited with a log (Ic₅₀) = –2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca²⁺ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca²⁺ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca²⁺ current inhibition was mediated by the Gα_i/o or Gα_q/11 family of subunits. Treatment with both PTX (Ca²⁺ current inhibition = 15.7 ± 10.6%, n = 8, P = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin’s effects on Ca²⁺ currents, as compared with control neurons (34.3 ± 18.9%, n = 8). These results indicate GHSR1a can couple to both Gα_i/o and Gα_q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca²⁺ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin’s regulation of gastric vagal afferents.

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures.

SUMMARY:

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated (ZFTA) (formerly v-rel avian reticuloendotheliosis viral oncogene [RELA]), or yes-associated protein 1 (YAP1) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA-fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1-fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA-fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal-MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies.

BackgroundCOVID-19 pandemic restrictions may have influenced behaviours related to weight.AimTo describe patterns of weight change among adults living in England with type 2 diabetes (T2D) and/or hypertension during the pandemic.Design and settingAn observational cohort study using the routinely collected health data of approximately 40% of adults living in England, accessed through the OpenSAFELY service inside TPP.MethodClinical and sociodemographic characteristics associated with rapid weight gain (>0.5 kg/m2/year) were investigated using multivariable logistic regression.ResultsData were extracted on adults with T2D (n = 1 231 455, 43.9% female, and 76.0% White British) or hypertension (n = 3 558 405, 49.7% female, and 84.3% White British). Adults with T2D lost weight overall (median δ = −0.1 kg/m2/year [interquartile range {IQR} −0.7–0.4]). However, rapid weight gain was common (20.7%) and associated with the following: sex (male versus female: adjusted odds ratio [aOR] 0.78 [95% confidence interval {CI} = 0.77 to 0.79]); age (older age reduced odds, for example, aged 60–69 years versus 18–29 years: aOR 0.66 [95% CI = 0.61 to 0.71]); deprivation (least deprived Index of Multiple Deprivation [IMD] quintile versus most deprived IMD quintile: aOR 0.87 [95% CI = 0.85 to 0.89]); White ethnicity (Black versus White: aOR 0.95 [95% CI = 0.92 to 0.98]); mental health conditions (for example, depression: aOR 1.13 [95% CI = 1.12 to 1.15]); and diabetes treatment (non-insulin treatment versus no pharmacological treatment: aOR 0.68 [95% CI = 0.67 to 0.69]). Adults with hypertension maintained stable weight overall (median δ = 0.0 kg/m2/year [IQR −0.6–0.5]); however, rapid weight gain was common (24.7%) and associated with similar characteristics as in T2D.ConclusionAmong adults living in England with T2D and/or hypertension, rapid pandemic weight gain was more common among females, younger adults, those living in more deprived areas, and those with mental health conditions.

The driverless vehicles still can't take L.A.'s notorious highways.

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HARI SREENIVASAN: The desire of the Kurds along Iraq’s northern border to govern themselves is receiving more resistance from Iraq’s central government. Iraqi army forces are demanding Kurdish troops withdraw from oil fields and military bases around Kirkuk, a city in the Kurdistan region that voted for independence last month. Kirkuk also has 10% of Iraq’s known oil reserves. Washington Post’s Loveday Morris is in Baghdad covering this standoff joins me now via Skype. First of all the significance of this. Why is it so important?

LOVEDAY MORRIS: There’s been a longtime conflict between Baghdad and Kurdistan over these disputed territories. Most significant of which is Kirkuk because of the oil reserves. But the referendum last month has really sharpened these disputes because you have Baghdad opposing independence and so it feels like they have to restate its territorial claims these areas. So that’s why we’re seeing a lot of tension right now.

HARI SREENIVASAN: And just to give people a little bit of a brief timeline – Iraqi forces control this area for a while and then in June ISIS took over the area and now it’s kind of back in Kurdish hands?

LOVEDAY MORRIS: Right. So in June 2014 Iraq lost control of a lot of the areas and we have this huge collapse in the face of an ISIS offensive. Over 100,000 soldiers fled and Kurdish forces moved in some of these areas – some of them maybe took from ISIS and others just moved into into the vacuum. And so Iraqi forces have been in these areas since June 2014. And that’s their main demand that they return to the areas.

HARI SREENIVASAN: What’s the likelihood that this standoff right now turns violent? Into some sort of a civil war?

LOVEDAY MORRIS:: I think at this point both sides don’t want violence. Al-Abadi, the prime minister, is really trying to defuse the situation by saying there’s going to be no military attack. But at the same time there is this buildup of forces so that I think they are trying to, in a way, intimidate the Kurds to withdraw from some areas but they don’t want to see a fight per say. But in this really tense situation there can be a small spark and things can turn violent quite easily.

HARI SREENIVASAN: Thank you.

The post Iraqi, Kurdish forces in standoff, weeks after Kurdish vote for independence appeared first on PBS NewsHour.

A new Nordic-style Open Kindergarten will be trialled in part of Scotland ahead of a potential roll-out across the country.

The accountancy firm has opened a new office in the Scottish town

Tam plays the waifu games for the "plot." Chris teaches his cats to play DDR. Kelley blames everyone else for her Vampire Survivors addiction.

The post RPG Cast – Episode 661: “I Got Addicted to the Pentagram” appeared first on RPGamer.

TWO banks have suspended London-based currency traders over the alleged manipulation of foreign exchange markets.

Journalists at CNN, including some of the network’s biggest personalities, are living in fear of “inevitable” layoffs and pay cuts as its new CEO looks to shore up finances amid declining ratings.

That’s according to The Ankler, which reported Wednesday that 77-year-old Chris Wallace—whose already been relegated to a weekend program—is among the network’s most well-known names whose future is in limbo.

Wallace’s $8.5 million contract, signed by the ex-CNN boss Jeff Zucker to recruit him away from Fox News three years ago, is reportedly up and he was spotted in CEO Mark Thompson’s office on Tuesday.

Read more at The Daily Beast.

I never completed the original Red Dead Redemption, but not for the usual reasons of being terrible at the game, or thinking that open worlds are too big and boring these days and I just want to lie down forever and watch anime. I never finished it because my Xbox 360 version was not, in practice, an open world game, but a lonely farm at the bottom of a vortex of butchered spacetime. In the prologue, reformed outlaw John Marston confronts an old bandit acquaintance and gets himself roundly shot to bits. He’s rescued by local rancher Bonnie MacFarlane, who nurses him back to health and gives him a few odd jobs to warm him up for the next plot point.

Read more

WASHINGTON — When Karen Pence found out that an art therapist in hurricane-ravaged Puerto Rico couldn’t afford the clay her clients needed, she sprang into action.

A trained watercolor artist and advocate of the little-known mental health profession, Vice President Mike Pence’s wife went to the Virginia art supply store she frequented when they lived in the state during his tenure in Congress, bought 120 pounds of self-drying clay and packed it aboard Air Force Two for their flight down to survey the damage.

“She cleaned him out,” the vice president said of the store’s owner.

Mrs. Pence made art therapy her cause ever since she first learned about it more than a decade ago. She has visited numerous art therapy programs, both in the U.S. and abroad, and on Wednesday in Florida, nine months into the administration, she planned to formally announce the goals for her art therapy initiative.

She wants to help people understand the difference between art therapy and arts and crafts, and to grasp that art therapy is a viable option for treating trauma, injury and other life experiences. She also wants to encourage young people to choose art therapy as a career.

“I don’t think that a lot of people understand the difference between therapeutic art and art therapy,” Mrs. Pence, a trained watercolor artist, told The Associated Press in an exclusive interview before the announcement at Florida State University in Tallahassee. The school has an art therapy program she described as “tremendous.”

Blabbing to a girlfriend can be therapeutic, she explained, but it is not the same as art therapy, which has three elements: a client, a trained therapist and art.

READ MORE: VP Pence’s wife aims to raise awareness about art therapy

As passionate as she is about raising art therapy’s profile, other issues help make Karen Pence tick, too.

One of them is helping military families, especially spouses. Her only son, Michael, is in the Marines.

There’s also her interest in honeybees. Mrs. Pence installed a beehive on the grounds of the U.S. Naval Observatory, where the vice president’s official residence is located, to help call attention to a decline in managed bee colonies that officials say could negatively affect U.S. agricultural production. She had a beehive at the Indiana governor’s residence for the same reason.

Now 60 and married to the vice president since 1985, Mrs. Pence has long been viewed as one of her husband’s most trusted political advisers. They are often together on trips, at the White House, or at the observatory, almost always holding hands.

Since returning to Washington in January (the family lived in the area when her husband served in Congress), she has accompanied the vice president on goodwill tours of Europe, Asia and Latin America, as well as trips to survey recent hurricane damage in Texas, Puerto Rico and the U.S. Virgin Islands. She tries to visit art therapy programs wherever she goes. Journalists who travel with Pence often keep an eye out for his wife; she often brings them cookies when he ventures back to the press cabin for small talk.

READ MORE: Devastated Puerto Rico needs unprecedented aid, says governor

She’s even done a little campaigning, urging Virginians to vote next month for Ed Gillespie in what’s viewed as a tight gubernatorial race.

“It really makes a difference, I can tell you. Nobody thought that we were going to win,” she said, an apparent reference to the Trump-Pence ticket.

The vice president often refers to his wife as the family’s “prayer captain.” She has led congregations in prayer during their hurricane-damage trips.

“We’re people of faith so we just try and approach everything with prayer,” Mrs. Pence said from her sunny, second-floor office in the Eisenhower Executive Office Building in the White House complex, where she and her staff enjoy coveted views of the Washington Monument and Jefferson Memorial. Art therapy drawings given as gifts adorn the outer office.

She proudly displayed several of her paintings, including of the Capitol dome, the vice president’s residence, a Ball canning jar-turned-flower vase, a cardinal bird and a pink peony. She turns many of her watercolors into prints and boxed notecards that she gifts to art therapists she meets.

Except for myriad pets, including two cats, a dog and a rabbit named Marlon Bundo, the Pences are empty nesters. Their son and two adult daughters are off on their own.

“I think for us this is a good time in our life for this role because our kids are out of college. They’re living their own lives,” Mrs. Pence said.

She’s also launching a blog in conjunction with Wednesday’s announcement to chronicle her visits to art therapy programs.

The post Karen Pence to outline goals for art therapy initiative appeared first on PBS NewsHour.

Finance guru Laura Pomfret explained how changes to inheritance tax in the budget may hit people in a way they hadn't realised

A powerful new AI called o1 is the most dangerous that OpenAI has ever released, the firm claims – but who are these warnings for, asks Chris Stokel-Walker

Scientists used AI to transform tourist photos into a 3D digital map of Antarctic penguin colonies – even as researchers debate whether to harness or discourage tourism in this remote region

Tigerair has again cancelled flights in and out of Denpasar, and there is no sign of the dispute being resolved.