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Toxoplasma gondii is an obligate intracellular parasite in the phylum Apicomplexa that causes toxoplasmosis in humans and animals worldwide. Despite its prevalence, there is currently no effective vaccine or treatment for chronic infection. Although there are therapies against the acute stage, prolonged use is toxic and poorly tolerated. This study aims to explore the potential of repurposing topotecan and 10-hydroxycamptothecin (HCPT) as drugs producing double strand breaks (DSBs) in T. gondii. DSBs are mainly repaired by Homologous Recombination Repair (HRR) and Non-Homologous End Joining (NHEJ). Two T. gondii strains, RHΔHXGPRT and RHΔKU80, were used to compare the drug's effects on parasites. RHΔHXGPRT parasites may use both HRR and NHEJ pathways but RHΔKU80 lacks the KU80 protein needed for NHEJ, leaving only the HRR pathway. Here we demonstrate that topotecan and HCPT, both topoisomerase I venoms, affected parasite replication in a concentration-dependent manner. Moreover, variations in fluorescence intensity measurements for the H2A.X phosphorylation mark (γH2A.X), an indicator of DNA damage, were observed in intracellular parasites under drug treatment conditions. Interestingly, intracellular replicative parasites without drug treatment show a strong positive staining for γH2A.X, suggesting inherent DNA damage. Extracellular (non-replicating) parasites did not exhibit γH2A.X staining, indicating that the basal level of DNA damage is likely to be associated with replicative stress. A high rate of DNA replication stress possibly prompted the evolution of an efficient repair machinery in the parasite, making it an attractive target. Our findings show that topoisomerase 1 venoms are effective antiparasitics blocking T. gondii replication.

This is the 12th in a series of salary surveys conducted at approximately 3-year intervals for toxicologists that began in 1988. Previous salary surveys were conducted in 1988,1 1991,2 1995,3 1998,4 2001,5 2004,6 2007 (which was posted electronically, but not published), 2012,7 2016,8 2020,9 and 2022.10 In addition to presenting the 2024 results, herein we are providing additional data and an analysis of the trends for employment and pay in toxicology over the last 37 years. [ABSTRACT FROM AUTHOR]

We report the discovery of COOL J0335−1927, a quasar at z = 3.27 lensed into three images with a maximum separation of 23.″3 by a galaxy cluster at z = 0.4178. To date, this is the highest redshift wide-separation lensed quasar known. In addition, COOL J0335−1927 shows several strong intervening absorbers visible in the spectra of all three quasar images with varying equivalent widths. The quasar also shows mini-broad line absorption. We construct a parametric strong gravitational lens model using ground-based imaging, constrained by the redshift and positions of the quasar images as well as the positions of three other multiply imaged background galaxies. Using our best-fit lens model, we calculate the predicted time delays between the three quasar images to be Δ t _AB = ${499}_{-146}^{+141}$ (stat) and Δ t _AC = $-{127}_{-17}^{+83}$ (stat) days. Folding in systematic uncertainties, the model-predicted time delays are within the ranges 240 < Δ t _AB < 700 and −300 < Δ t _AC < −30. We also present g -band photometry from archival Dark Energy Camera Legacy Survey and Pan-STARRS imaging, and new multi-epoch observations obtained between 2022 September 18 UT and 2023 February 22 UT, which demonstrate significant variability in the quasar and will eventually enable the measurement of the time delay between the three quasar images. The currently available light curves are consistent with the model-predicted time delays. This is the fifth paper from the COOL-LAMPS collaboration.

The article discusses Indiana Supreme Court (ISC) and Indiana Court of Appeals decisions on cases concerning banking, business, and contract law between September 1, 2022 and August 31, 2023. Topics explored include the establishment of commercial courts in several counties in Indiana, the business principle of fiduciary duty acknowledged in the case Zanetis v. Bradburn, and the rules governing guaranties noted in the case Shoaff v. First Merchants Bank.

The article discusses amendments to the Uniform Commercial Code (UCC) of several U.S. states to accommodate emerging technologies such as artificial intelligence (AI), virtual currency, and distributed ledger technology. It explored the appointment of a Joint Committee by the Uniform Law Commission (ULC) and the American Law Institute (ALI) to review the proposed amendments, the acknowledgment of electronic commerce developments, and the revision of several terms outlined in the UCC.

The article discusses the rulings by the Indiana Supreme Court and Court of Appeals in areas of banking, business and contract law from September 2021 to August 2022. Other topics include Indiana's summary judgment standard, the Supreme Court's commercial courts initiative, and the statewide online court case management system called Odyssey.

Objectives: An analysis of the risk factors and seasonal and spatial distribution of individuals with subclinical malaria in hypoendemic Bangladesh was performed. Methods: From 2009 to 2012, active malaria surveillance without regard to symptoms was conducted on a random sample (n = 3971) and pregnant women (n = 589) during a cohort malaria study in a population of 24 000. Results: The overall subclinical Plasmodium falciparum malaria point prevalence was 1.0% (n = 35), but was 3.2% (n = 18) for pregnant women. The estimated incidence was 39.9 per 1000 person-years for the overall population. Unlike symptomatic malaria, with a marked seasonal pattern, subclinical infections did not show a seasonal increase during the rainy season. Sixty-nine percent of those with subclinical P. falciparum infections reported symptoms commonly associated with malaria compared to 18% without infection. Males, pregnant women, jhum cultivators, and those living closer to forests and at higher elevations had a higher prevalence of subclinical infection. Conclusions: Hypoendemic subclinical malaria infections were associated with a number of household and demographic factors, similar to symptomatic cases. Unlike clinical symptomatic malaria, which is highly seasonal, these actively detected infections were present year-round, made up the vast majority of infections at any given time, and likely acted as reservoirs for continued transmission.

This is the eleventh in a series of salary surveys for toxicologists conducted at three-year intervals that began in 1988. Previous salary surveys were conducted in 1988, 1991, 1995, 1998, 2001, 2004, 2007 (which was posted electronically, but not published), 2012, 2016 and 2020. In addition to presenting the 2022 results, herein we are providing additional data and an analysis of the trends for employment and pay in toxicology over the last 35 years. The eleventh Triennial Toxicology Salary Survey was conducted as a joint project by the American College of Toxicology (ACT) and the Society of Toxicology (SOT). In addition to the two parent organizations, eight others (the Society for Birth Defects Research, the Society of Toxicologic Pathology, the Safety Pharmacology Society, the American Board of Toxicology (ABT), the Academy of Toxicological Sciences, the Roundtable of Toxicology Consultants, the Society of Environmental Toxicology and Chemistry (SETAC), and the Environmental Mutagenesis and Genomics Society) supported the effort by distributing the Survey Monkey-based instrument to their memberships. Surveys were not distributed to regional SOT chapters, causing there to be minimal responses below the doctorate and master's degree levels. It should be noted that there continues to be a significant increase in the number of individuals reporting six-figure incomes and in those receiving significant sums as bonuses. [ABSTRACT FROM AUTHOR]

Early in the COVID-19 pandemic, medical care providers at an acute illness hospital received increasing numbers of post-acute advanced COVID-19 patients from referring hospitals where they were showing no signs of improvement after receiving treatments from standard Emergency Use Authorization (EUA)-type protocols. The care providers turned to repurposing medications to treat these patients and added hydroxyurea, a medication commonly used for treating sickle cell anemia, to the hospital’s COVID-19 treatment protocol and began to see notable clinical improvements. As the pandemic continued and new concerns arose concerning COVID-19 complications, those same care providers again turned to repurposing drugs. Focusing on the neuromuscular effects seen in COVID-19 patients, care providers turned to medications used to treat chronic neuromuscular conditions. Post-acute advanced Covid-19 patients initially received an abbreviated course of hydroxyurea followed by titrated doses of pyridostigmine. Positive responses were noted with cognition, diminished oxygen demands, progressive decrease in ventilator support, improved swallowing, and mobility. The authors suggest repurposed drugs could have great utility for treating COVID-19. It is recommended larger, COVID-19 clinical trials be completed to include hydroxyurea and pyridostigmine for validating the outcomes and clinical observations seen in these presented cases. [ABSTRACT FROM AUTHOR]

Parasite differentiation from proliferating tachyzoites into latent bradyzoites is central to pathogenesis and transmission of the intracellular protozoan pathogen Toxoplasma gondii. The presence of bradyzoite-containing cysts in human hosts and their subsequent rupture can cause life-threatening recrudescence of acute infection in the immunocompromised and cyst formation in other animals contributes to zoonotic transmission and widespread dissemination of the parasite. In this review, we discuss the evidence showing how the clinically relevant process of bradyzoite differentiation is regulated at both transcriptional and post-transcriptional levels. Specific regulatory factors implicated in modulating bradyzoite differentiation include promoter-based cis-elements, epigenetic modifications and protein translation control through eukaryotic initiation factor -2 (eIF2). In addition to a summary of the current state of knowledge in these areas we discuss the pharmacological ramifications and pose some questions for future research.