Mode of action studies confirm on-target engagement of lysyl-tRNA synthetase inhibitor and lead to new selection marker for Cryptosporidium.

Introduction: Cryptosporidiosis is a leading cause of diarrheal-associated morbidity and mortality, predominantly affecting children under 5 years old in low-and-middle-income countries. There is no effective treatment and no vaccine. New therapeutics are emerging from drug discovery efforts. It is critical that mode of action studies are performed alongside drug discovery to ensure the best clinical outcomes. Unfortunately, technology to identify and validate drug targets for Cryptosporidium is severely lacking. Methods: We used C. parvum lysyl-tRNA synthetase (CpKRS) and DDD01510706 as a target-compound pair to develop both chemical and genetic tools for mode of action studies for Cryptosporidium. We adapted thermal proteome profiling (TPP) for Cryptosporidium, an unbiased approach for target identification. Results: Using TPP we identified the molecular target of DDD01510706 and confirm that it is CpKRS. Genetic tools confirm that CpKRS is expressed throughout the life cycle and that this target is essential for parasite survival. Parasites genetically modified to over-express CpKRS or parasites with a mutation at the compound-binding site are resistant to treatment with DDD01510706. We leveraged these mutations to generate a second drug selection marker for genetic modification of Cryptosporidium, KRSR. This second selection marker is interchangeable with the original selection marker, NeoR, and expands the range of reverse genetic approaches available to study parasite biology. Due to the sexual nature of the Cryptosporidium life cycle, parental strains containing different drug selection markers can be crossed in vivo. Discussion: Selection with both drug markers produces highly efficient genetic crosses (>99% hybrid progeny), paving the way for forward genetics approaches in Cryptosporidium.

Retracted Covid-19 articles: significantly more cited than other articles within their journal of origin.

With the expansion of research volume, coinciding with the age of the internet, the retraction of published papers from scientific journals has become crucial to preserving scientific integrity. Since the beginning of the COVID-19 pandemic, both public and professional interest in scientific literature has grown as people attempt to educate themselves on the virus. The Retraction Watch Database COVID-19 blog was accessed in June and November of 2022 and analyzed to ensure articles met inclusion criteria. Articles were then accessed on Google Scholar and the Scopus database to find number of citations and SJR/CiteScore. The average SJR and CiteScore for a journal that published one of the articles was 1.531 and 7.3 respectively. The retracted articles were cited an average of 44.8 times, which was significantly higher than the average CiteScore (p = 0.01). Between June and November, retracted COVID-19 articles gained a total of 728 new citations, presence of "withdrawn" or "retracted" before article title did not affect citation rates. COPE guidelines for retraction statements were not met for 32% of articles. We believe retracted COVID-19 publications may have been more likely to include bold claims that garnered a disproportionately high amount of attention within the scientific community. Additionally, we found many journals were not forthright with explanations for why articles had been retracted. Retractions could be a tool used to add to the scientific discourse, but currently we are only getting half the data, the what and not the why.

A Surgical Perspective on the Association between Cystic Lesions of the Pineal Gland (Descartes' Seat of the Soul) and the Pituitary (the Master Gland).

Introduction Rene Descartes (1596-1650), the famous philosopher and scientist, identified the pineal gland as the only cerebral structure not represented bilaterally, the "seat of the soul"; and the source of rational thought. Pineal cysts (PCs) are often incidentally identified in MRI studies, with a reported prevalence of 1 to 4.3%. Rathke cleft cysts (RCCs) are pituitary lesions accounting for <1% of intracranial masses. There are scant data in the literature addressing any association between these two midline cystic lesions. Methods We reviewed the medical records of patients presenting at our institution from April 2008 through February 2020, whose records indicated a diagnosis of RCC, and those whose records included pineal lesions. Our objective was to evaluate the association between these two midline lesions. Brain MRI studies were reviewed for the presence of PCs; only patients with PCs that measured ≥5 mm in diameter were included. Results We identified 116 patients with RCCs, and 34 patients with PCs, treated from April 2008 through February 2020. Among the RCC group, 14/116 patients (12%) had PCs. Among the PC group, 3/34 patients (8.8%) had RCCs. Overall, 17 patients (11.3%) had concomitant RCCs and PCs. The mean maximal diameter of the PCs was 7.5 mm (range = 5-17 mm), whereas the mean maximal diameter of RCCs was 13 mm (range = 5-40 mm). Conclusion The incidental diagnosis of cystic lesions of the pineal and pituitary gland is increasingly reported, primarily because of advances in current diagnostic modalities. Our data demonstrated no clear consensual association between pineal and pituitary cysts.