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The global crisis of untreatable microbial infections necessitates the design of new antibiotics. Drug repurposing is a promising strategy for expanding the antibiotic repertoire. In this study, we repurpose the clinically approved anticancer agent cisplatin into a targeted antibiotic by conjugating its Pt­(IV) prodrug to enterobactin (Ent), a triscatecholate siderophore employed by Enterobacteriaceae for iron (Fe) acquisition. The l-Ent-Pt­(IV) conjugate (l-EP) exhibits antibacterial activity against Escherichia coli K12 and the uropathogenic isolate E. coli CFT073. Similar to cisplatin, l-EP causes a filamentous morphology in E. coli and initiates lysis in lysogenic bacteria. Studies with E. coli mutants defective in Ent transport proteins show that Ent mediates the delivery of l-EP into the E. coli cytoplasm, where reduction of the Pt­(IV) prodrug releases the cisplatin warhead, causing growth inhibition and filamentation of E. coli. Substitution of Ent with its enantiomer affords the d-Ent-Pt­(IV) conjugate (d-EP), which displays enhanced antibacterial activity, presumably because d-Ent cannot be hydrolyzed by Ent esterases and thus Fe cannot be released from this conjugate. E. coli treated with l/d-EP accumulate ≥10-fold more Pt as compared to cisplatin treatment. By contrast, human embryonic kidney cells (HEK293T) accumulate cisplatin but show negligible Pt uptake after treatment with either conjugate. Overall, this work demonstrates that the attachment of a siderophore repurposes a Pt anticancer agent into a targeted antibiotic that is recognized and transported by siderophore uptake machinery, providing a design strategy for drug repurposing by siderophore modification and heavy-metal “trojan-horse” antibiotics.

Functional connectivity analysis has become a powerful tool for probing the human brain function and its breakdown in neuropsychiatry disorders. So far, most studies adopted resting-state paradigm to examine functional connectivity networks in the brain, thanks to its low demand and high tolerance that are essential for clinical studies. However, the test-retest reliability of resting-state connectivity measures is moderate, potentially due to its low behavioral constraint. On the other hand, naturalistic neuroimaging paradigms, an emerging approach for cognitive neuroscience with high ecological validity, could potentially improve the reliability of functional connectivity measures. To test this hypothesis, we characterized the test-retest reliability of functional connectivity measures during a natural viewing condition, and benchmarked it against resting-state connectivity measures acquired within the same functional magnetic resonance imaging (fMRI) session. We found that the reliability of connectivity and graph theoretical measures of brain networks is significantly improved during natural viewing conditions over resting-state conditions, with an average increase of almost 50% across various connectivity measures. Not only sensory networks for audio-visual processing become more reliable, higher order brain networks, such as default mode and attention networks, but also appear to show higher reliability during natural viewing. Our results support the use of natural viewing paradigms in estimating functional connectivity of brain networks, and have important implications for clinical application of fMRI. Hum Brain Mapp 38:2226-2241, 2017. © 2017 Wiley Periodicals, Inc.

Functional connectivity analysis has become a powerful tool for probing the human brain function and its breakdown in neuropsychiatry disorders. So far, most studies adopted resting state paradigm to examine functional connectivity networks in the brain, thanks to its low demand and high tolerance that are essential for clinical studies. However, the test-retest reliability of resting state connectivity measures is moderate, potentially due to its low behavioral constraint. On the other hand, naturalistic neuroimaging paradigms, an emerging approach for cognitive neuroscience with high ecological validity, could potentially improve the reliability of functional connectivity measures. To test this hypothesis, we characterized the test-retest reliability of functional connectivity measures during a natural viewing condition, and benchmarked it against resting state connectivity measures acquired within the same functional magnetic resonance imaging (fMRI) session. We found that the reliability of connectivity and graph theoretical measures of brain networks is significantly improved during natural viewing conditions over resting state conditions, with an average increase of almost 50% across various connectivity measures. Not only sensory networks for audio-visual processing become more reliable, higher order brain networks, such as default mode and attention networks, also appear to show higher reliability during natural viewing.

Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in the fight against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action. We also discuss the different synthetic strategies in producing teixobactin and its analogues, and the structure-activity relationship (SAR) studies.

The crucial role of the cerebellum in motor learning and coordination is very well known. Considerable interest has recently shifted toward its contribution to nonmotor tasks, such as working memory, emotion, and language. However, the cognitive role and functional subdivisions of the cerebellum, particularly in dynamic, ecologically realistic contexts, are not yet established. By analyzing functional neuroimaging data acquired while participants viewed a short dramatic movie, we found that posterior and inferior cerebellar regions are reliably engaged in dynamic perceptual and affective processes with no explicit motor component. These cerebellar regions show significant relevance to visual salience and unexpected turning points of the movie. Our results demonstrate that distinct functional subdivisions of the cerebellum are robustly engaged in real-life cognitive processes, playing specific roles through a dynamic interaction with higher order regions in the cerebral cortex.

Human interactions with the world are influenced by memories of recent events. This effect, often triggered by perceptual cues, occurs naturally and without conscious effort. However, the neuroscience of involuntary memory in a dynamic milieu has received much less attention than the mechanisms of voluntary retrieval with deliberate purpose. Here, we investigate the neural processes driven by naturalistic cues that relate to, and presumably trigger the retrieval of recent experiences. Viewing the continuation of recently viewed clips evokes greater bilateral activation in anterior hippocampus, precuneus and angular gyrus than naïve clips. While these regions manifest reciprocal connectivity, continued viewing specifically modulates the effective connectivity from the anterior hippocampus to the precuneus. The strength of this modulation predicts participants’ confidence in later voluntary recall of news details. Our study reveals network mechanisms of dynamic, involuntary memory retrieval and its relevance to metacognition in a rich context resembling everyday life.