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Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis. A series of compounds are discovered for the treatment of visceral leishmaniasis, and cdc2-related kinase 12 (CRK12) is identified as the probable primary drug target.

Visceral leishmaniasis (VL) causes significant mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. We describe the development of a novel anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of VL, has suitable physicochemical, pharmacokinetic and toxicological properties for further development and has been declared a preclinical candidate. Detailed mode of action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a novel, druggable, target for VL.

Copy number variants (CNVs) are regions of the genome that vary in integer copy number. CNVs, which comprise both amplifications and deletions of DNA sequence, have been identified across all domains of life, from bacteria and archaea to plants and animals. CNVs are an important source of genetic diversity, and can drive rapid adaptive evolution and progression of heritable and somatic human diseases, such as cancer. However, despite their evolutionary importance and clinical relevance, CNVs remain understudied compared to single-nucleotide variants (SNVs). This is a consequence of the inherent difficulties in detecting CNVs at low-to-intermediate frequencies in heterogeneous populations of cells. Here, we discuss molecular methods used to detect CNVs, the limitations associated with using these techniques, and the application of new and emerging technologies that present solutions to these challenges. The goal of this short review and perspective is to highlight aspects of CNV biology that are understudied and define avenues for further research that address specific gaps in our knowledge of these complex alleles. We describe our recently developed method for CNV detection in which a fluorescent gene functions as a single-cell CNV reporter and present key findings from our evolution experiments in Saccharomyces cerevisiae . Using a CNV reporter, we found that CNVs are generated at a high rate and undergo selection with predictable dynamics across independently evolving replicate populations. Many CNVs appear to be generated through DNA replication-based processes that are mediated by the presence of short, interrupted, inverted-repeat sequences. Our results have important implications for the role of CNVs in evolutionary processes and the molecular mechanisms that underlie CNV formation. We discuss the possible extension of our method to other applications, including tracking the dynamics of CNVs in models of human tumors.

Copy number variants (CNVs) are a pervasive source of genetic variation and evolutionary potential, but the dynamics and diversity of CNVs within evolving populations remain unclear. Long-term evolution experiments in chemostats provide an ideal system for studying the molecular processes underlying CNV formation and the temporal dynamics with which they are generated, selected, and maintained. Here, we developed a fluorescent CNV reporter to detect de novo gene amplifications and deletions in individual cells. We used the CNV reporter in Saccharomyces cerevisiae to study CNV formation at the GAP1 locus, which encodes the general amino acid permease, in different nutrient-limited chemostat conditions. We find that under strong selection, GAP1 CNVs are repeatedly generated and selected during the early stages of adaptive evolution, resulting in predictable dynamics. Molecular characterization of CNV-containing lineages shows that the CNV reporter detects different classes of CNVs, including aneuploidies, nonreciprocal translocations, tandem duplications, and complex CNVs. Despite GAP1's proximity to repeat sequences that facilitate intrachromosomal recombination, breakpoint analysis revealed that short inverted repeat sequences mediate formation of at least 50% of GAP1 CNVs. Inverted repeat sequences are also found at breakpoints at the DUR3 locus, where CNVs are selected in urea-limited chemostats. Analysis of 28 CNV breakpoints indicates that inverted repeats are typically 8 nucleotides in length and separated by 40 bases. The features of these CNVs are consistent with origin-dependent inverted-repeat amplification (ODIRA), suggesting that replication-based mechanisms of CNV formation may be a common source of gene amplification. We combined the CNV reporter with barcode lineage tracking and found that 102-104 independent CNV-containing lineages initially compete within populations, resulting in extreme clonal interference. However, only a small number (18-21) of CNV lineages ever constitute more than 1% of the CNV subpopulation, and as selection progresses, the diversity of CNV lineages declines. Our study introduces a novel means of studying CNVs in heterogeneous cell populations and provides insight into their dynamics, diversity, and formation mechanisms in the context of adaptive evolution.

Approximately 1000 children are born every year in the United States with one effective cardiac pumping chamber, or single ventricle heart disease. One of the early causes of mortality in this population is pulmonary arteriovenous malformations (PAVMs), which allow blood to bypass gas exchange in the lungs. PAVMs most frequently occur in children after superior cavopulmonary anastomosis (SCPA), a procedure that redirects venous blood from the upper body to the lungs. Because plasma proteins are in part responsible for directing angiogenesis, we hypothesized that differential protein concentrations would be observed in superior caval blood among children after SCPA according to PAVM status. We performed quantitative plasma proteomics from 11 children with PAVMs and in seven children without PAVMs; an additional 11 children with Fontan circulation were included as a reference. Among children with SCPA, there were no significant differences in the plasma proteomes for those with and without PAVMs. When comparing children with Fontan circulation to those with SCPA and PAVMs, 18 proteins exhibited differential expression (10 downregulated and eight upregulated) in superior caval plasma. These results suggest that factors other than, or in addition to, plasma proteins may be responsible for single ventricle patients’ susceptibility to PAVMs after SCPA. Impact What is the key message of your article? We did not identify significant differences in plasma proteins when comparing those children with and without pulmonary arteriovenous malformations (PAVMs) after superior cavopulmonary anastomosis (SCPA). What does it add to the existing literature? The etiology of PAVMs in this population is likely due to factors other than, or in addition to, differences in plasma proteins. What is the impact? Further studies are needed to identify causes of PAVMs among children after SCPA.

Pinus radiata (radiata pine or Monterey pine) is threatened in its native range in California and, at the same time, one of the most widely-planted tree species worldwide, especially in the southern hemisphere. It is affected by a wide range of plant-feeding insects both in its native range and in regions where it is planted as an introduced tree. In addition, there are many invasive insects that have colonised P. radiata , in some cases causing major damage. Here, our objectives were to provide a complete and up-to-date overview of all insect species recorded from P. radiata worldwide, to summarise where these insects are native and which countries or regions they have invaded, to categorise them according to their impacts as damaging species or as vectors of plant pathogens, and to examine border interceptions to determine whether pathways exist that would allow these species to enter and potentially invade additional regions. Our compilation of insects feeding on P. radiata provides a list of 649 species (and an additional 11 species identified at the genus level only). Coleoptera is the most represented order in the list (299 species), followed by Lepidoptera (224 species) and Hemiptera (65 species). We classified 28 species as high-impact, including 12 true bark beetles (Coleoptera: Curculionidae: Scolytinae), eight Lepidoptera, five other Coleoptera, two Hymenoptera and one Hemiptera. These species can cause substantial direct damage or act as vectors of highly-damaging plant pathogens. Other species cause only occasional damage, rarely requiring management (classified as ‘low-medium impact’) or they are generally benign (‘negligible impact’). Hemiptera and Scolytinae have a high proportion of species established outside their native range. The Nearctic and Neotropic regions have been invaded by the most high-impact species, mainly by species native to Europe. Border interceptions of 185 species (29% of those on our list) were recorded during import inspections between 1995–2021, indicating considerable potential for further invasions. The findings of our study can be used to identify potential high-impact invaders and the pathways that may require more phytosanitary attention. Furthermore, our analyses provide useful insights into the insect-plant interactions resulting from the global distribution of a tree species and the native and non-native insects feeding on it.

Classical biological control is being attempted for the giant willow aphid, Tuberolachnus salignus (Gmelin) (Hemiptera: Aphididae: Lachninae), an invasive pest first recorded in New Zealand in 2013. Giant willow aphid (GWA) feeds primarily on species of Salix , and is also occasionally recorded on species of Populus , Malus and Pyrus in New Zealand where it is causing problems ranging from detrimental impacts on willow trees and honey bees, to honey losses, rising vespid wasp populations and risks to fruit exports. A biological control programme against GWA was initiated by importing into containment a parasitoid wasp, Pauesia nigrovaria (Provancher) (Hymenoptera: Braconidae: Aphidiinae), reared from GWA in California, USA. Host range testing was conducted using five non-target aphid species, including representatives of all aphid subfamilies and tribes in New Zealand that contain any native species (all are distantly related to the target host, GWA), as well as a closely related exotic pest species, Cinara fresai , in the same subfamily as the target host (Lachninae). No-choice tests were negative for all non-target species. A single P. nigrovaria individual attempted to attack two C. fresai during behavioural assays. However these actions did not result in reproductive success. Our results demonstrate that P. nigrovaria is a host specific parasitoid and its release into the New Zealand environment poses negligible environmental risk.

Research has been unsuccessful at revealing an analogue to curriculum-based measurement in the area of progress monitoring for social behavior. As a result, there is a need to develop change-sensitive, technically adequate, feasible progress monitoring tools for social behavior that represent general outcome measures of performance. The purpose of this research was to develop and evaluate the technical adequacy of a brief behavior rating scale (BBRS) that contained change-sensitive rating items. Using data from a randomized controlled study, extant rating scales were analyzed according to four change-sensitive metrics to detect a pool of rating items for inclusion in a BBRS. Next, successive iterations of BBRSs were analyzed to determine how few items a BBRS is capable of containing while maintaining adequate reliability and criterion-related validity. Results revealed that the change-sensitive metrics successfully identified several items upon which students demonstrated change in response to an intervention. Also, results indicated that a BBRS can have as few as 12 items and maintain adequate reliability and criterion relatedness. The implications of these results and directions for research on the use of BBRSs as progress monitoring tools for social behavior are discussed.

More women are leading schools in the role of superintendent, but numbers are still low when compared to men. There is limited research connecting women superintendents and the promotion of other women to leadership positions. Archival data from Texas schools showed that there is no difference between districts led by women superintendents or males for percentages of women central office leaders.