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Rationally designed novel Phenyloxazoline Synthase Inhibitors: chemical synthesis and biological evaluation to accelerate the discovery of new antimycobacterial antibiotics
Get PDFThe uncontrolled spread of drug-resistant tuberculosis (DR-TB) clinical cases necessitates the urgent discovery of newer chemotypes with novel mechanisms of action. Here, we report the chemical synthesis of rationally designed novel transition-state analogues (TSAs) by targeting the cyclization (Cy) domain of phenyloxazoline synthase (MbtB), a key enzyme of the conditionally essential siderophore biosynthesis pathway. Following bio-assay-guided evaluation of TSA analogues preferentially in iron-deprived and iron-rich media to understand target preferentiality against a panel of pathogenic and non-pathogenic mycobacteria strains, we identified a hit, i.e., TSA-5. Molecular docking, dynamics, and MMPBSA calculations enabled us to comprehend TSA-5’s stable binding at the active site pocket of MbtB_Cy and the results imply that the MbtB_Cy binding pocket has a strong affinity for electron-withdrawing functional groups and contributes to stable polar interactions between enzyme and ligand. Furthermore, enhanced intracellular killing efficacy (8 μg/mL) of TSA-5 against Mycobacterium aurum in infected macrophages is noted in comparison to moderate in vitro antimycobacterial efficacy (64 μg/mL) against M. aurum. TSA-5 also demonstrates whole-cell efflux pump inhibitory activity against Mycobacterium smegmatis. Identification of TSA-5 by focusing on the modular MbtB_Cy domain paves the way for accelerating novel anti-TB antibiotic discoveries
Blindsight
No full textCollected Stories is, as implied by the title, a collection of stories, curated by Ben Rivers. Fiction and poetry have always been an essential source of inspiration for his filmmaking. On the occasion of the retrospective Ghost Strata, and other stories, held at Jeu de Paume in Paris in November 2023, he decided to bring his films in conversation with writers who have influenced him over the years.
Rivers invited fourteen authors to watch one of his films and respond in writing in any way they wished. Imaginative and surprising, the fables, essays and poems of Collected Stories come together in a beautiful celebration of the work of one of contemporary cinema’s vital artists, doubling as a testament to the reciprocal nature of inspiration
Test Reuse based on adaptive semantic matching across Android mobile applications
No full textAutomatic test generation can help verify and develop the behavior of mobile applications. Test reuse based on semantic similarities between applications of the same category has been utilized to reduce the manual effort of Graphical User Interface (GUI) testing. However, most of the existing studies fail to solve the semantic problem of event matching, which leads to the failure of test reuse. To overcome this challenge, we propose TRASM (Test Reuse based on Adaptive Semantic Matching), a test reuse approach based on adaptive strategies to find a better event matching across android mobile applications. TRASM first performs GUI events deduplication on the initial test set obtained from test generation, and then employs an adaptive strategy to find better event matching, which enables reusing the existing test. Preliminary experiments with comparison to baseline methods on 15 applications demonstrate that TRASM can improve the precision of GUI event matching while reducing the failure of test reuse and the running time required for test reuse
The October Revolution and the competing projects of Soviet state-building on the western border (Ukraine and Belarus)
Get PDFThe February Revolution marked the starting point of a complicated
social, political and economic transformation across the former Russian
Empire. The subsequent October Revolution and Russian civil war put different projects of national state-building on trial. The rivalry between these different forms of statehood became especially severe at the Western margins of the former Empire, divided by the front lines of the First World War. In Belarus, partly occupied by the German Army since mid-1915, national activism was weak and often supported by external forces: the German administration, the Bolsheviks and later the Second Polish Republic. With an underdeveloped grassroots national movement, neither the Belarusian People’s Republic (BNR), first declared on 25 March 1918, nor the Belarusian Soviet Socialist Republic (BSSR), established on 1 January 1919, could claim to fully represent the population of Belarus. Contrarily, in Ukraine, local actors became the most ardent promoters of self-rule and state independence. The first post-revolutionary years were thus defined by the rivalry between the Ukrainian People’s Republic (UNR), formed on 7 November 1917, and the Soviet Republic in Ukraine which had existed under various names since December 1917. The period 1917–1920 was to be, by far, the most turbulent in the political history of these two republics
Argument and explanation
Get PDFIn this paper, we bring together two closely related,
but distinct, notions: argument and explanation.
We clarify their relationship. We then provide an
integrative review of relevant research on these
notions, drawn both from the cognitive science and
the AI literatures.We then use this material to identify
key directions for future research, indicating areas
where bringing together cognitive science and AI
perspectives would be mutually beneficial
Differences in Intrinsic Gray-Matter connectivity and their genomic underpinnings in Autism Spectrum Disorder
Get PDFBackground: Autism is a heterogenous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in ‘intrinsic’ (i.e. gray-matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs.
Methods: Here, we examined intrinsic global and local wiring costs in the brain of N=359 autistic individuals and N=279 controls, aged 7-31 years from the EU-AIMS Longitudinal European Autism Project (LEAP). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray-matter. Vertex-wise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allan Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings.
Results: Group differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes previously implicated in the etiology of autism at the genetic and transcriptomic level.
Conclusion: Based on intrinsic gray-matter connectivity, the study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches
Tracing changes in the citing practices of a master’s student: a longitudinal case study
Get PDFThis longitudinal case study aimed to trace changes in the citing practices of a master’s student during a one-year course of study at a UK university. Multiple sources of data (samples of the participant’s writing, markers’ reports and lecturers’ feedback, repeated interviews with the participant, university documentation) were used in multiple data collection waves during three distinct periods within the academic year: a 5-week pre-sessional academic English course, the taught part of the master’s program, and the supervised dissertation. The study documented changes in the participant’s citing patterns and her understanding of citing. The overall picture is of a non-linear, uneven development, marked by simultaneous acquisition of more complex citing practices and fluctuation in the already adopted ones. The findings reveal the complex nature of citing, whose mastery requires effective coordination of multiple domains: discursive (e.g., use of reporting verbs), conceptual (e.g., awareness of the rhetorical purposes of citations) and technical (e.g., accurate use of citation styles). This implies that teaching citation should target both students’ discursive practices and their awareness of citing
Evaluation of a team-based collection and delivery operation
Get PDFThe rise in the volume of e-commerce is adding increasing pressure on the logistics of parcel delivery. To improve the efficiency of their operations, the parcel industry in Japan is exploring team-based collection and delivery (TCD), whereby the sales driver (SD) hands out parcels to the field crews (FC), who subsequently deliver them to the door. However, the efficiency of TCD is still understudied. This study proposes a method for optimizing the delivery route for TCD and evaluates the efficiency of the ongoing operation. The TCD delivery problem focuses on minimizing the task completion time using parameters derived through surveys of the actual operations. Comparison between seven different methods show that the newly proposed method of fuzzy c-means clustering with a genetic algorithm outperforms the rest, rapidly computing sufficiently accurate results. Results suggest that the proposed optimal route reduces the total delivery time by up to 18.7%. However, the amount of time saved varies considerably by the area and the number of parcels delivered. Additional constraints for improving driver safety, the cost-benefit of increasing FCs, and the impact on the environmental cost are also considered. The proposed method also helps spread the workload and the travel time of the FCs more evenly, thus further reducing the total delivery time
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