Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site.

Chromosome segregation begins when the cysteine protease, separase, cleaves the Scc1 subunit of cohesin at the metaphase-to-anaphase transition. Separase is inhibited prior to metaphase by the tightly bound securin protein, which contains a pseudosubstrate motif that blocks the separase active site. To investigate separase substrate specificity and regulation, here we develop a system for producing recombinant, securin-free human separase. Using this enzyme, we identify an LPE motif on the Scc1 substrate that is distinct from the cleavage site and is required for rapid and specific substrate cleavage. Securin also contains a conserved LPE motif, and we provide evidence that this sequence blocks separase engagement of the Scc1 LPE motif. Our results suggest that rapid cohesin cleavage by separase requires a substrate docking interaction outside the active site. This interaction is blocked by securin, providing a second mechanism by which securin inhibits cohesin cleavage

Alabaster glory.

Alabaster Glory includes three installations in the gallery space: 望(wàng), 盛(chéng), and 余(yú). These components represent three stages of human life: the beginning, living on this earth, and the end. The core concept behind the three stages is the relationship between the creator (God) and creations, referring to humans that live in this broken world containing suffering, chaos, crime, conflict, or the personal experience of an inner void. Alabaster Glory invites viewers to walk through the space first to encounter a magnitude of infant heart forms placed by a window, which intends to evoke curiosity about their quantity and symbolism. Once viewers have immersed themselves within the installation, they will experience light projected from broken vessels to reflect upon: Would you expect to see the light inside or outside the vessels? Would you expect the vessels to project light or cast only shadows? Finally, the last stage of Alabaster Glory consists of dust, ashes, and one alabaster heart on top. It is located on the opposite end of the gallery from the two thousand hearts, and compels the viewers to ponder: What is the ultimate desire and treasure that will not fade away and remain at the end of life

ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia

USP34 regulates endothelial PAR1 mRNA transcript expression and cellular signaling

Signaling by G protein-coupled receptors (GPCRs) is regulated by temporally distinct processes including receptor desensitization, internalization, and lysosomal sorting, and are tightly controlled by posttranslational modifications. While the role of phosphorylation in regulating GPCR signaling is well studied and established, the mechanisms by which other posttranslational modifications, such as ubiquitination, regulate GPCR signaling are not clearly defined. We hypothesize that GPCR ubiquitination and deubiquitination is critical for proper signaling and cellular responses. In the present study, we show that the deubiquitinase ubiquitin-specific protease-34 (USP34) regulates thrombin-stimulated protease-activated receptor-1 (PAR1)-induced p38 autophosphorylation and activation. The PAR1-stimulated p38 signaling pathway is driven by ubiquitination. Interestingly, small interfering RNA-induced knockdown of USP34 expression markedly increased PAR1 cell surface abundance and protein expression without modulating PAR1 ubiquitination or the ubiquitination status of p38 signaling pathway components. In addition, increased PAR1 expression observed in USP34-depleted cells was not caused by altered PAR1 constitutive internalization, agonist-induced internalization, or receptor degradation. Rather, we report that loss of USP34 expression increased mRNA transcript expression of the PAR1-encoding gene, F2R. This study unexpectedly identified a critical role for USP34 in regulation of F2R mRNA transcript expression, which modulates PAR1 cell surface levels and thrombin-stimulated p38 mitogen-activated protein kinase signaling

Testing the Extremes of Initial Mass Function Variability using Compact Stellar Systems

The initial mass function (IMF) is a cornerstone in star formation and galaxy evolution studies. It has traditionally been assumed to be universal, but this has been challenged by increasingly detailed observations of diverse, extragalactic stellar populations. However, this observed variability in the IMF is debated as a sufficient theoretical framework to explain it has not yet been substantiated. A major limitation is that these observations have only probed narrow regions of mass-metallicity-density parameter space (i.e. metal-rich, early-type galaxies). We present an unprecedented sample of integrated light spectroscopy of diverse objects, including "compact" stellar systems (CSSs, i.e. globular clusters and ultra-compact dwarf galaxies) and brightest cluster galaxies. Our sample covers a wide range of metallicities (-1.7 < [Fe/H] < 0.01) and velocity dispersions (7.4 km/s < σ < 275 km/s). We carefully reduce high S/N Keck LRIS spectra and measure the IMF by employing a new suite of full-spectrum stellar population synthesis models. These simultaneously fit for ages, metallicities, and detailed chemical abundances, allowing us to robustly measure the effects of the IMF. We show that CSSs do not follow trends with physical parameters that have been found for early-type galaxies (ETGs). In particular, previously established metallicity-dependent trends with the IMF may change in complex ways. We examine potential factors that could be causing the population of CSSs to contrast with the ETGs in this parameter space

Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model

Cannabidiol is a promising potential therapeutic for neurodegenerative diseases, including Alzheimer’s disease (AD). Our laboratory has shown that oral CBD treatment prevents cognitive impairment in a male genetic mouse model of AD, the amyloid precursor protein 1 x presenilin 1 hemizygous (APPxPS1) mouse. However, as sex differences are evident in clinical populations and in AD mouse models, we tested the preventive potential of CBD therapy in female APPxPS1 mice. In this study, 2.5-month-old female wildtype-like (WT) and APPxPS1 mice were fed 20 mg/kg CBD or a vehicle via gel pellets daily for 8 months and tested at 10.5 months in behavioural paradigms relevant to cognition (fear conditioning, FC; cheeseboard, CB; and novel object recognition test, NORT) and anxiety-like behaviours (elevated plus maze, EPM). In the CB, CBD reduced latencies to find a food reward in APPxPS1 mice, compared to vehicle-treated APPxPS1 controls, and this treatment effect was not evident in WT mice. In addition, CBD also increased speed early in the acquisition of the CB task in APPxPS1 mice. In the EPM, CBD increased locomotion in APPxPS1 mice but not in WT mice, with no effects of CBD on anxiety-like behaviour. CBD had limited effects on the expression of fear memory. These results indicate preventive CBD treatment can have a moderate spatial learning-enhancing effect in a female amyloid-β-based AD mouse model. This suggests CBD may have some preventive therapeutic potential in female familial AD patients

Psychological traits and public attitudes towards abortion: the role of empathy, locus of control, and need for cognition

In the summer of 2022, the U.S. Supreme Court overturned the historic Roe v. Wade ruling, prompting various states to put forth ballot measures regarding state-level abortion rights. While earlier studies have established associations between demographics, such as religious beliefs and political ideologies, and attitudes toward abortion, the current research delves into the role of psychological traits such as empathy, locus of control, and need for cognition. A sample of 294 U.S. adults was obtained via Amazon Mechanical Turk, and participants were asked to provide their attitudes on seven abortion scenarios. They also responded to scales measuring empathy toward the pregnant woman and the unborn, locus of control, and need for cognition. Principal Component Analysis divided abortion attitudes into two categories: traumatic abortions (e.g., pregnancies due to rape) and elective abortions (e.g., the woman does not want the child anymore). After controlling for religious belief and political ideology, the study found psychological factors accounted for substantial variation in abortion attitudes. Notably, empathy toward the pregnant woman correlated positively with abortion support across both categories, while empathy toward the unborn revealed an inverse relationship. An internal locus of control was positively linked to support for both types of abortions. Conversely, external locus of control and need for cognition only positively correlated with attitudes toward elective abortion, showing no association with traumatic abortion attitudes. Collectively, these findings underscore the significant and unique role psychological factors play in shaping public attitudes toward abortion. Implications for research and practice were discussed

Improving Strength Properties of Paper Utilizing Mycelia Fungus

Alternatives to the traditional sack grade of paper used for grocery bags was investigated for use in the commercial market. This project investigated the use of mycelium in conjunction with wood-based pulps to produce a structurally enhanced paper sheet. The study included creating and testing a fibrous sheet containing a network of mycelium. Three mycelium types were used: Reishi (Ganoderma Lucidum), Pearl (Pleurotus Ostreatus var. Columbus), and Enoki (Flammulina Velutipes). All three require similar growth conditions but have different growth patterns. Three major trials were run, providing the mycelium with different growth conditions and medium. The first was a simple inoculation. The second was an inoculation of filter paper that was then stored in petri dishes to help reduce the mold growth discovered in the first trial. And the third was an inoculation of pulp slurries that were left to grow before being converted into small sheets. The slurry samples were made with both bleached and unbleached pulp to see if the type of pulp affected the growth. The mechanical properties of the developed materials were evaluated and compared to control samples of each pulp medium. Testing of the mycelium sheets was minimal because of poor growth, mold buildup, and an insubstantial number of samples per trial. Visual inspection under a microscope with 2x magnification and low angle light revealed areas of shiny, hairlike tendrils, protruding off the surface. In some cases, the tendrils appeared to grow over dark mold spots. Under visual inspection only, Pearl had the most clear and substantial growth. After visual inspection, the sheets were tested mechanically in hopes of more sufficient data; the grammage and tensile strength were measured. Strength comparisons were separated based on the inoculation method--inoculated onto pre-formed sheets or added to pulp slurry. The collected data indicated that Reishi grown on bleached pulp was the strongest. In general, inoculated samples of pulp turned out stronger than the original or plain sheets for bleached pulp and weaker for unbleached pulp

Integrity in the Age of AI: Ethical Considerations of ChatGPT Use Among De La Salle University Senior High School Students

The rise and integration of AI tools like ChatGPT in education raises significant ethical concerns, namely regarding academic integrity. This study investigates the use and ethical implications of ChatGPT among senior high school students at De La Salle University Manila through a descriptive cross-sectional design. 226 student responses from a structured survey revealed how these tools affect views on academic integrity and actual academic practices. Findings indicate that while ChatGPT boosts academic productivity in various tasks, such as research, comprehension, and content creation, it also introduces risks concerning dependency, originality, and fairness. Moreover, many students believe that said risks can be mitigated through responsible usage but also express concerns over ChatGPT undermining academic integrity. That said, this study highlights the urgent need for clear guidelines and robust educational programs to harness AI\u27s benefits while still maintaining academic standards. The results underscore the need for a balanced approach to integrating AI, guaranteeing ethical considerations are addressed alongside technological advancements