Praziquantel represents the frontline chemotherapy used to treat schistosomiasis, a neglected tropical disease (NTD) caused by infection with macro-parasitic blood fluke schistosomes. While this drug ...is safe, its inability to kill all schistosome lifecycle stages within the human host often requires repeat treatments. This limitation, amongst others, has led to the search for novel anti-schistosome replacement or combinatorial chemotherapies. Here, we describe a repositioning strategy to assess the anthelmintic activity of epigenetic probes/inhibitors obtained from the Structural Genomics Consortium.
Thirty-seven epigenetic probes/inhibitors targeting histone readers, writers and erasers were initially screened against Schistosoma mansoni schistosomula using the high-throughput Roboworm platform. At 10 μM, 14 of these 37 compounds (38%) negatively affected schistosomula motility and phenotype after 72 hours of continuous co-incubation. Subsequent dose-response titrations against schistosomula and adult worms revealed epigenetic probes targeting one reader (NVS-CECR2-1), one writer (LLY-507 and BAY-598) and one eraser (GSK-J4) to be particularly active. As LLY-507/BAY-598 (SMYD2 histone methyltransferase inhibitors) and GSK-J4 (a JMJD3 histone demethylase inhibitor) regulate an epigenetic process (protein methylation) known to be critical for schistosome development, further characterisation of these compounds/putative targets was performed. RNA interference (RNAi) of one putative LLY-507/BAY-598 S. mansoni target (Smp_000700) in adult worms replicated the compound-mediated motility and egg production defects. Furthermore, H3K36me2, a known product catalysed by SMYD2 activity, was also reduced by LLY-507 (25%), BAY-598 (23%) and siSmp_000700 (15%) treatment of adult worms. Oviposition and packaging of vitelline cells into in vitro laid eggs was also significantly affected by GSK-J4 (putative cell permeable prodrug inhibitor of Smp_034000), but not by the related structural analogue GSK-J1 (cell impermeable inhibitor).
Collectively, these results provide further support for the development of next-generation drugs targeting schistosome epigenetic pathway components. In particular, the progression of histone methylation/demethylation modulators presents a tractable strategy for anti-schistosomal control.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Teucrium yemense (Defl), locally known as Reehal Fatima, is a medicinal plant commonly grown in Saudi Arabia and Yemen. Phytochemical investigation of the aerial parts of T. yemense yielded six new ...neoclerodane diterpenoids, namely fatimanol A–E (1, 2, 3, 5, and 6) and fatimanone (4), and the known teulepicephin (7). As both the Teucrium genus and the related Lamiaceae family have previously been widely reported to possess anthelmintic and antimicrobial activities, the structural and biological characterization of the seven diterpenoids was pursued. The structures of the new compounds were elucidated from their 2D NMR and MS profiles and by comparison to related compounds. The structure of fatimanol D (5) was confirmed by X-ray crystallographic analysis. The new structures contribute to the breadth of knowledge of secondary metabolites in this genus.
The 2019 novel coronavirus disease (COVID-19) has broadly impacted our daily lives. Here, we used a longitudinal approach to investigate older adults’ mood and expectations regarding aging before and ...during the global pandemic (Study 1). We also examined age differences in mood, expectations regarding aging, COVID-19 attitudes, and loneliness using a cross-sectional approach (Study 2). In Study 1, older adults completed a mood and expectations regarding aging survey up to 2 years prior to the pandemic and again in April, 2020 (during the pandemic). Participants also completed surveys regarding COVID-19 attitudes and loneliness. In Study 2, a United States sample of younger and older adults completed these surveys during the pandemic. Older adults’ mood and expectations regarding aging remained fairly constant, and younger adults showed lower mood and expectations regarding aging than did older adults, despite older adults showing greater concern about COVID-19. Overall, we find that some older adults seem to be resilient with respect to their mood and expectations regarding aging. These findings reveal important preliminary implications for how older adults may be impacted as a result of lifestyle changes necessary for well-being and the well-being of society.
A Nation of Laws, and Race Laws Banks, Nina; Whatley, Warren C.
Journal of economic literature,
06/2022, Letnik:
60, Številka:
2
Journal Article
Recenzirano
This article reviews the history of race laws in the United States as distinct from the rule of law, an idea found in the writing and speeches of Sadie Tanner Mossell Alexander, the first African ...American PhD in economics (1921). We review the race laws of slavery, lynching, Negro Jobs, and the making of the Black ghetto. We highlight the life and writings of Alexander and other early African American economists as an example of the cost of racial exclusion in the economics profession and how it has impeded the production of useful knowledge about the workings of the US economy. (JEL J15, K38, N31, N32, N41, N42)
The Gun-Slave Hypothesis is the long-standing idea that European gunpowder technology played a key role in growing the transatlantic slave trade. I combine annual data from the Transatlantic Slave ...Trade Database and the Anglo–African Trade Statistics to estimate a Vector Error Correction Model of the 18th century British slave trade that captures four versions of the Gun-Slave Hypothesis: guns-for-slaves-in-exchange, guns-for-slaves-in-production, slaves-for-guns-derived and the gun-slave cycle. Three econometric results emerge. (1) Gunpowder imports and slave exports were co-integrated in a long-run equilibrium relationship. (2) Positive deviations from equilibrium gunpowder “produced” additional slave exports. This guns-for-slaves-in-production result survives 17 placebo tests that replace gunpowder with non-lethal commodities imports. It is also confirmed by an instrumental variables estimation that uses excess capacity in the British gunpowder industry as an instrument for gunpowder. (3) Additional slave exports attracted additional gunpowder imports for 2–3 more years. Together these dynamics formed a gun-slave cycle. Impulse-response functions generate large increases in slave export in response to increases in gunpowder imports. I use these results to explain the growth of slave exports along the Guinea Coast of Africa in the 18th century.
The coronavirus disease 2019 (COVID-19) is one of the biggest recent threats to public health. People rely on news for up-to-date information during such major events, but news is often emotional in ...nature, which can affect how we learn and remember information. Additionally, graphs are widely used in news, but comprehension and memory for graphical information can be influenced by various factors, including emotions. We tested how the emotional framing of news would affect graphical memory across the lifespan. Participants studied a graph showing the number of weekly or daily new COVID-19 deaths after reading COVID-19 news framed as more positive or negative. Participants also reported their attitudes toward the pandemic, political leaning, news consumption habits, mood, and need for cognition. There was no overall difference in memory across conditions or age, but memory was more biased by the emotional framing of the news when the graphs were less visually complex. A number of exploratory correlations are also discussed. The findings indicate that framing news with a more positive or negative lens can bias understanding of and memory for related graphical information in some cases and can have implications for improving media literacy and public health compliance.
Older adults experience deficits in associative memory. However, age-related differences are reduced when information is consistent with prior knowledge (i.e., schematic support), suggesting that ...episodic and semantic memory are interrelated. It is unclear what role metacognitive processes play in schematic support. Prior knowledge may reduce encoding demands, but older adults may allocate cognitive resources to schema-consistent information because it is more meaningful. We examined metacognitive awareness of and control over associative information that was consistent or inconsistent with prior knowledge. In Experiment 1, participants self-paced their study of grocery items paired with either market prices or unusually high prices and were tested on the exact price of each item over four study-test lists with new items on each list. In Experiment 2, participants studied items for a fixed time but made judgments of learning (JOLs) at encoding. Older adults better remembered the prices of market-value items than overpriced items. In Experiment 1, younger and older adults studied overpriced items longer than market-priced items, consistent with a discrepancy reduction model of self-regulated learning, but study time did not relate to later recall accuracy, suggesting a labor-in-vain effect. In Experiment 2, participants gave higher JOLs to market-priced items than overpriced items and were generally metacognitively aware of the benefits of schematic support. Together, these results suggest that the benefits of schematic support may not be dependent on or influenced by metacognitive control processes, supporting the hypothesis that episodic memory may be less distinct from semantic memory in younger and older adults.
Older adults may experience certain forms of cognitive decline, but some forms of semantic memory remain intact in older age. To address how metaphor comprehension changes with age and whether ...metaphor comprehension relies more heavily on analogical reasoning (supported by fluid intelligence) or on conceptual combination (supported by crystalized intelligence), we compared performance of younger and older adults. In two experiments, healthy older adults (54–88 years) scored lower on a measure of fluid intelligence (Ravens Progressive Matrices) but higher on a measure of crystalized intelligence (Mill Hill Vocabulary Test) relative to younger adults (18–34 years). Groups were equally successful in comprehending relatively easy metaphors (Study 1), but older adults showed a striking advantage over younger adults for novel literary metaphors (Study 2). Mixed-effects modeling showed that measures of fluid and crystalized intelligence each made separable contributions to metaphor comprehension for both groups, but older adults relied more on crystalized intelligence than did younger adults. These age-related dissociations clarify cognitive effects of aging and highlight the importance of crystalized intelligence for metaphor comprehension in both younger and older adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved) (Source: journal abstract)
The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC50 = 19.1 μM) and Fasciola hepatica ...(IC50 = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto-sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto-sempervirol (IC50 ≈ 6 μM for larval blood flukes; IC50 ≈ 3 μM for juvenile liver flukes) and moderate selectivity (SI ≈ 4–5 for blood flukes, 8–13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad-spectrum anthelmintic.
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•30 analogues of the anthelmintic diterpenoid 7-keto-sempervirol were synthesised.•Analogues were screened against S. mansoni and F. hepatica juvenile and adult stages.•Compound 7d showed improved dual anthelmintic activity over 7-keto-sempervirol.•Compound 7d inhibited egg production and affected surface tegument integrity.
Our memory for common, easily recognizable logos, like the Apple logo, is surprisingly poor because of attentional saturation, where we stop attending to details of frequently encountered objects. ...This lack of attention to details may leave us susceptible to misinformation effects. Across four experiments, we tested recognition memory for the Apple logo after incidentally encoding an accurate or altered version of the logo (Experiments 1–3), or after no incidental encounter of the logo prior to the surprise test (Experiment 4). Additionally, participants rated how much they liked the logo as a measure of processing fluency. Results demonstrated that incidentally viewing an altered version of the Apple logo can disrupt subsequent recognition of the correct logo, but this effect may diminish following a short delay. Considering our frequent exposure to everyday stimuli, we show conditions in which memory for a ubiquitous stimulus can be disrupted when incidentally presented with inaccurate information.
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