Conspectus The defining feature of the Nazarov cyclization is a 4π-conrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides ...access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process. The first stage involves a 4π-electrocyclization leading to the formation of an allylic cation, and the second stage corresponds to the fate of this cationic intermediate. With a complete understanding of the discrete events that characterize the overall process, one can optimize reactivity and control the selectivity of the different Stage 2 pathways. In this Account, we describe the development of methods that render the Nazarov cyclization catalytic and chemoselective, focusing specifically on advances made in our lab between 2002 and 2015. The initial discovery made in our lab involved reactions of electronically asymmetric (“polarized”) substrates, which cyclize efficiently in the catalytic regime using mild Lewis acidic reagents. These cyclizations also exhibit selective eliminative behavior, increasing their synthetic utility. Research directed toward catalytic asymmetric Nazarov cyclization led to the serendipitous discovery of a 4π-cyclization coupled to a well-behaved Wagner–Meerwein rearrangement, representing an underexplored Stage 2 process. With careful choice of promoter and loading, it is possible to access either the rearrangement or the elimination pathway. Additional experimental and computational studies provided an effective model for anticipating the migratory behavior of substiutents in the rearrangements. Problem-solving efforts prompted investigation of alternative methods for generating pentadienyl cation intermediates, including oxidation of allenol ethers and addition of nucleophiles to dienyl diketones. These Nazarov cyclization variants afford cyclopentenone products with vicinal stereogenic centers and a different arrangement of substituents around the ring. A nucleophilic addition/cyclization/elimination sequence can be executed enantioselectively using catalytic amounts of a nonracemic chiral tertiary amine. In summary, the discovery and development of several new variations on the Nazarov electrocyclization are described, along with synthetic applications. This work illustrates how strongly substitution patterns can impact the efficiency of the 4π-electrocyclization (Stage 1), allowing for mild Lewis acid catalysis. Over the course of these studies, we have also identified new ways to access the critical pentadienyl cation intermediates and demonstrated strategies that exploit and control the different cationic pathways available post-electrocyclization (Stage 2 processes). These advances in Nazarov chemistry were subsequently employed in the synthesis of natural product targets such as (±)-merrilactone A, (±)-rocaglamide, and (±)-enokipodin B.
Purpose Racial/ethnic disparities in cancer survival in the United States are well documented, but the underlying causes are not well understood. We quantified the contribution of tumor, treatment, ...hospital, sociodemographic, and neighborhood factors to racial/ethnic survival disparities in California. Materials and Methods California Cancer Registry data were used to estimate population-based cancer-specific survival for patients diagnosed with breast, prostate, colorectal, or lung cancer between 2000 and 2013 for each racial/ethnic group (non-Hispanic black, Hispanic, Asian American and Pacific Islander, and separately each for Chinese, Japanese, and Filipino) compared with non-Hispanic whites. The percentage contribution of factors to overall racial/ethnic survival disparities was estimated from a sequence of multivariable Cox proportional hazards models. Results In baseline models, black patients had the lowest survival for all cancer sites, and Asian American and Pacific Islander patients had the highest, compared with whites. Mediation analyses suggested that stage at diagnosis had the greatest influence on overall racial/ethnic survival disparities accounting for 24% of disparities in breast cancer, 24% in prostate cancer, and 16% to 30% in colorectal cancer. Neighborhood socioeconomic status was an important factor in all cancers, but only for black and Hispanic patients. The influence of marital status on racial/ethnic disparities was stronger in men than in women. Adjustment for all covariables explained approximately half of the overall survival disparities in breast, prostate, and colorectal cancer, but it explained only 15% to 40% of disparities in lung cancer. Conclusion Overall reductions in racial/ethnic survival disparities were driven largely by reductions for black compared with white patients. Stage at diagnosis had the largest effect on racial/ethnic survival disparities, but earlier detection would not entirely eliminate them. The influences of neighborhood socioeconomic status and marital status suggest that social determinants, support mechanisms, and access to health care are important contributing factors.
Intercropping is a farming practice involving two or more crop species, or genotypes, growing together and coexisting for a time. On the fringes of modern intensive agriculture, intercropping is ...important in many subsistence or low‐input/resource‐limited agricultural systems. By allowing genuine yield gains without increased inputs, or greater stability of yield with decreased inputs, intercropping could be one route to delivering ‘sustainable intensification’. We discuss how recent knowledge from agronomy, plant physiology and ecology can be combined with the aim of improving intercropping systems. Recent advances in agronomy and plant physiology include better understanding of the mechanisms of interactions between crop genotypes and species – for example, enhanced resource availability through niche complementarity. Ecological advances include better understanding of the context‐dependency of interactions, the mechanisms behind disease and pest avoidance, the links between above‐ and below‐ground systems, and the role of microtopographic variation in coexistence. This improved understanding can guide approaches for improving intercropping systems, including breeding crops for intercropping. Although such advances can help to improve intercropping systems, we suggest that other topics also need addressing. These include better assessment of the wider benefits of intercropping in terms of multiple ecosystem services, collaboration with agricultural engineering, and more effective interdisciplinary research.
The diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) can be difficult, but the real-time quaking-induced conversion (RT-QuIC) assays have made a considerable impact on its clinical diagnosis. ...This technique exploits the ability of the misfolded pathological form of prion protein (PrP
) found in cerebrospinal fluid (CSF) to induce conversion of normal PrP to the misfolded form, which subsequently aggregates. The formation of these aggregates of misfolded PrP is monitored in real time using fluorescent dyes. The current sensitivity of CSF RT-QuIC undertaken at the UK National CJD Research & Surveillance Unit is 92% and the specificity is 100%. The interpretation of the RT-QuIC traces is affected by the presence of raised CSF red and white cells counts and elevated total protein concentrations. We recommend that CSF samples for RT-QuIC analysis are clear and colourless with a white cell count of <10 x10^6/L and have a total protein concentration of <1 g/L.
•We propose VP-Nets for brain structure localization in 3D fetal neurosonography.•The proposed 2.5D CNN is memory efficient, producing a high resolution 3D output.•Our model can handle structure ...overlap while keeping contextual information.•Visualization of the trained VP-Nets is described.•VP-Nets is compared with Random Forests and 3D U-Nets.
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Three-dimensional (3D) fetal neurosonography is used clinically to detect cerebral abnormalities and to assess growth in the developing brain. However, manual identification of key brain structures in 3D ultrasound images requires expertise to perform and even then is tedious. Inspired by how sonographers view and interact with volumes during real-time clinical scanning, we propose an efficient automatic method to simultaneously localize multiple brain structures in 3D fetal neurosonography. The proposed View-based Projection Networks (VP-Nets), uses three view-based Convolutional Neural Networks (CNNs), to simplify 3D localizations by directly predicting 2D projections of the key structures onto three anatomical views.
While designed for efficient use of data and GPU memory, the proposed VP-Nets allows for full-resolution 3D prediction. We investigated parameters that influence the performance of VP-Nets, e.g. depth and number of feature channels. Moreover, we demonstrate that the model can pinpoint the structure in 3D space by visualizing the trained VP-Nets, despite only 2D supervision being provided for a single stream during training. For comparison, we implemented two other baseline solutions based on Random Forest and 3D U-Nets. In the reported experiments, VP-Nets consistently outperformed other methods on localization. To test the importance of loss function, two identical models are trained with binary corss-entropy and dice coefficient loss respectively. Our best VP-Net model achieved prediction center deviation: 1.8 ± 1.4 mm, size difference: 1.9 ± 1.5 mm, and 3D Intersection Over Union (IOU): 63.2 ± 14.7% when compared to the ground truth. To make the whole pipeline intervention free, we also implement a skull-stripping tool using 3D CNN, which achieves high segmentation accuracy. As a result, the proposed processing pipeline takes a raw ultrasound brain image as input, and output a skull-stripped image with five detected key brain structures.
Molecular mechanisms of antibiotic resistance Blair, Jessica M A; Webber, Mark A; Baylay, Alison J ...
Nature reviews. Microbiology,
01/2015, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, ...many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
An animal’s survival depends on its ability to correctly evaluate sensory stimuli and select appropriate behavioral responses. When confronted with ambiguous stimuli, the brain is faced with the task ...of selecting one action while suppressing others. Although conceptually simple, the site and substrate of this elementary form of decision making is still largely unknown. Zebrafish larvae respond to a moving dot stimulus in either of two ways: a small object (potential prey) evokes approach, whereas a large object (potential predator) is avoided. The classification of object size relies on processing in the optic tectum. We genetically identified a population of cells, largely comprised of glutamatergic tectal interneurons with non-stratified morphologies, that are specifically required for approach toward small objects. When these neurons are ablated, we found that the behavioral response is shifted; small objects now tend to elicit avoidance. Conversely, optogenetic facilitation of neuronal responses with channelrhodopsin (ChR2) enhances approaches to small objects. Calcium imaging in head-fixed larvae shows that a large proportion of these neurons are tuned to small sizes. Their receptive fields are shaped by input from retinal ganglion cells (RGCs) that are selective for prey identity. We propose a model in which valence-based decisions arise, at a fundamental level, from competition between dedicated sensorimotor pathways in the tectum.
•Decision between approach versus avoidance of moving objects requires the tectum•Ablation of a subset of interneurons increases avoidance of small moving objects•Optogenetic facilitation of these neurons enhances approach to small moving objects•Interneurons that exhibit narrow size tuning receive input from prey-selective RGCs
Barker and Baier use a visually mediated behavior to investigate sensorimotor decision making in the larval zebrafish. They identity specific interneurons in the optic tectum that bias behavioral choice to approaches. These neurons are tuned to a narrow range of sizes and have receptive fields shaped by prey-selective retinal ganglion cell inputs.
Animals use the sense of vision to scan their environment, respond to threats, and locate food sources. The neural computations underlying the selection of a particular behavior, such as escape or ...approach, require flexibility to balance potential costs and benefits for survival. For example, avoiding novel visual objects reduces predation risk but negatively affects foraging success. Zebrafish larvae approach small, moving objects (“prey”) and avoid large, looming objects (“predators”). We found that this binary classification of objects by size is strongly influenced by feeding state. Hunger shifts behavioral decisions from avoidance to approach and recruits additional prey-responsive neurons in the tectum, the main visual processing center. Both behavior and tectal function are modulated by signals from the hypothalamic-pituitary-interrenal axis and the serotonergic system. Our study has revealed a neuroendocrine mechanism that modulates the perception of food and the willingness to take risks in foraging decisions.
•Feeding state influences approach versus avoidance decisions in zebrafish•Hunger alters the neural representation of prey-like stimuli in the tectum•The neuroendocrine and serotonergic systems mediate the modulation by feeding state
Filosa et al. show that hunger enhances the decision by larval zebrafish to approach (versus avoid) moving visual objects and the processing of prey cues in the tectum through signals from the hypothalamic-pituitary-interrenal axis and serotonergic system.
A new study has identified two distinct pup vocalizations in deer mice, showing that discrete genetic loci explain the acoustic variation between these two call types and that the calls elicit ...different levels of maternal responsiveness.
A new study has identified two distinct pup vocalizations in deer mice, showing that discrete genetic loci explain the acoustic variation between these two call types and that the calls elicit different levels of maternal responsiveness.
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