Cells assemble and maintain functionally distinct actin cytoskeleton networks with various actin filament organizations and dynamics through the coordinated action of different sets of actin-binding ...proteins. The biochemical and functional properties of diverse actin-binding proteins, both alone and in combination, have been increasingly well studied. Conversely, how different sets of actin-binding proteins properly sort to distinct actin filament networks in the first place is not nearly as well understood. Actin-binding protein sorting is critical for the self-organization of diverse dynamic actin cytoskeleton networks within a common cytoplasm. Using in vitro reconstitution techniques including biomimetic assays and single-molecule multi-color total internal reflection fluorescence microscopy, we discovered that sorting of the prominent actin-bundling proteins fascin and α-actinin to distinct networks is an intrinsic behavior, free of complicated cellular signaling cascades. When mixed, fascin and α-actinin mutually exclude each other by promoting their own recruitment and inhibiting recruitment of the other, resulting in the formation of distinct fascin- or α-actinin-bundled domains. Subdiffraction-resolution light microscopy and negative-staining electron microscopy revealed that fascin domains are densely packed, whereas α-actinin domains consist of widely spaced parallel actin filaments. Importantly, other actin-binding proteins such as fimbrin and espin show high specificity between these two bundle types within the same reaction. Here we directly observe that fascin and α-actinin intrinsically segregate to discrete bundled domains that are specifically recognized by other actin-binding proteins.
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•Purified bundling proteins intrinsically sort within reconstituted actin networks•Fascin and α-actinin segregate to F-actin bundles with different filament spacing•Fascin and α-actinin facilitate their own binding while inhibiting the other•The compact bundlers fascin, espin, and fimbrin co-segregate away from α-actinin
Winkelman et al. address how actin-binding proteins segregate to functionally distinct F-actin networks. They show that purified F-actin-bundling proteins contain intrinsic properties that are sufficient to drive their sorting to distinct reconstituted F-actin networks by establishing particular network architectures.
Crizotinib inhibits various kinases, including ALK and ROS1. In a patient with lung cancer and an activating ROS1 rearrangement, resistance to crizotinib developed early, owing to a mutation that ...inhibited binding of the drug a few residues away from the classic gatekeeper site.
Since the pivotal discovery of imatinib as a safe and effective drug for the treatment of chronic myeloid leukemia,
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kinase inhibitors have emerged as powerful agents in the treatment of several cancers. The identification of activating mutations within the kinase domain of the epidermal growth factor receptor (EGFR)
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has led to the widespread use of kinase inhibitors in this genetically defined subset of lung cancers.
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More recently, chromosomal translocations that create fusion proteins involving the tyrosine kinase domains of ALK
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or ROS1
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have been the subject of intense investigation in lung adenocarcinoma because of the availability of clinically active . . .
A hydrogen borrowing reaction employing secondary alcohols and Ph* (Me5C6) ketones to give β-branched carbonyl products is described (21 examples). This new C–C bond forming process requires low ...loadings of Cp*IrCl22, relatively low temperatures, and up to 2.0 equiv of the secondary alcohol. Substrate-induced diastereoselectivity was observed, and this represents the first example of a diastereoselective enolate hydrogen borrowing alkylation. By utilizing the Ph* group, the β-branched products could be straightforwardly cleaved to the corresponding esters or amides using a retro-Friedel–Crafts reaction. Finally, this protocol was applied to the synthesis of fragrance compound (±)-3-methyl-5-phenylpentanol.
Although considerable research has been done on memory for temporal information, as well as on the relationship between context and cognition, not much is known about the influence of temporal ...context on memory formation and retention. In this study, given that our sample comes from a largely Roman Catholic population, we used religious practices that occur throughout the calendar year to operationalize temporal context into two religious seasons (Lent and Ordinary Time). In addition, we used religious art to assess experience and memory as a function of whether there was temporal congruity or incongruity. This allowed us to explore different levels of memory representation; namely, memory for perceptual details of the art, memory for more inferential understanding of the art, and autobiographical memory for the initial experience of the art. Participants viewed 22 representational and abstract artworks during either Lent or Ordinary Time. After viewing, memory was tested at immediate, 1-day, and 7-day delays. We expected that the congruent temporal context (i.e., Lent) would lead to more activated semantic knowledge, which would then aid memory encoding and retention. This was the case only for perceptual details of the art. In addition, during Lent, forgetting followed a more linear pattern. These results suggest that priming semantic knowledge through temporal context leads encoding to focus on low-level information, as opposed to the processing of more complex information. Overall, these findings suggest that temporal context can influence cognition, but to a limited extent.
In this multicenter trial, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant survival benefit in comatose children who survived in-hospital cardiac ...arrest.
Therapeutic hypothermia for comatose adults who have had an out-of-hospital cardiac arrest was recommended on the basis of results of clinical trials reported in 2002.
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More recent trials have shown that fever prevention with therapeutic normothermia is equally efficacious as therapeutic hypothermia in adult and pediatric populations.
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Current guidelines recommend either hypothermia or normothermia for temperature management after out-of-hospital cardiac arrest in adults and children.
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In-hospital cardiac arrest in children commonly results in death or in a poor long-term functional outcome in survivors; however, outcomes in the in-hospital setting are significantly better than those in the out-of-hospital . . .
A vinyl cyclopropane rearrangement embedded in an iridium‐catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo‐defined cyclopentanes from Ph* methyl ketone and ...cyclopropyl alcohols. Mechanistic studies provide evidence for the ring‐expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl‐substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.
A vinyl cyclopropane/cyclopentene rearrangement process has been embedded in an iridium‐catalyzed hydrogen borrowing reaction, enabling the formation of substituted, stereo‐defined cyclopentanes containing up to four contiguous stereogenic centres—all from reaction of pentamethylphenyl (Ph*) methylketone and a variety of cyclopropyl alcohols.
Cyclopropanes are highly useful motifs that are often incorporated into drug candidates to improve potency, metabolic stability, or pharmacokinetic properties. An expedient method for the ...α-cyclopropanation of ketones using hydrogen borrowing (HB) catalysis is described. The transformation occurs via HB alkylation of a hindered ketone with subsequent intramolecular displacement of a pendant leaving group affording the cyclopropanated product. The leaving group can be installed in either the ketone or alcohol component of the HB system, giving access to α-cyclopropyl ketones via two complementary approaches. Conversion to the corresponding carboxylic acids can be achieved in a simple two-step sequence to afford synthetically useful 1,1-substituted spirocyclopropyl acid building blocks.
Enantioselective Synthesis of Sealutomicin C Astle, Stuart M.; Guggiari, Sean; Frost, James R. ...
Journal of the American Chemical Society,
07/2024, Letnik:
146, Številka:
26
Journal Article
Recenzirano
Odprti dostop
The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B–D). Herein we report the development of an ...enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.
IMPORTANCE: Little is known about neuropsychological outcomes of children who survived pediatric cardiac arrest (CA). OBJECTIVE: To describe the neuropsychological outcomes of CA survivors enrolled ...in the Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) and Out-of-Hospital (THAPCA-OH) trials and compare the results with the primary outcome measure for these trials. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of 222 CA survivors aged 1 to 18 years who received chest compressions for 2 minutes or more, remained comatose and required mechanical ventilation after return of circulation, and were enrolled in targeted temperature-management trials from 41 pediatric intensive care units. Data were collected from September 3, 2009, to February 3, 2016, and analyzed from March 10, 2017, to April 20, 2018. MAIN OUTCOMES AND MEASURES: The Vineland Adaptive Behavior Scales, Second Edition (VABS-II), a standardized measure of neurobehavioral functioning based on caregiver report (age-corrected mean SD scores = 100 15), was used to evaluate pre-CA functioning within 24 hours after enrollment; VABS-II<70 indicated significant developmental delays; VABS-II and neuropsychological testing were completed 1 year after CA. Neuropsychological testing included the Mullen Scales of Early Learning (Mullen) for children younger than 6 years and the Wechsler Abbreviated Scale of Intelligence (WASI) and neuropsychological measures of attention, memory, processing speed, and executive functioning for older children. RESULTS: Of 160 participants who completed neuropsychological testing, 96 (60.0%) were male; the median (interquartile range IQR) age was 2.5 years (1.3-6.1 years). Ninety-six (60.0%) were white, 41 (25.6%) were black, and 23 (14.4%) were of other/unknown race; 343 (21.2%) were Hispanic or Latino; 119 (74.4%) were non-Hispanic or Latino; and 7 (4.4%) were of unknown ethnicity. One hundred fourteen participants (71.2%) were classified as having favorable outcomes (VABS-II ≥70). Impairments (>2 SD below the mean for age) across neuropsychological measures ranged from 7% to 61%. Correlations between global cognitive and VABS-II scores were strong for younger children (Mullen, r = 0.69-0.87) but moderate for older children (r = 0.21-0.54 for the WASI). Of 111 children with favorable outcomes on VABS-II, 25.2% had global cognitive impairment and 30 of 35 older children (85.7%) had selective neuropsychological deficits. CONCLUSIONS AND RELEVANCE: In this prospectively evaluated cohort of pediatric CA survivors who were initially comatose, although 71.2% were classified as having favorable outcomes, significant neuropsychological deficits were identified in pediatric CA survivors who were classified as having favorable outcomes. The findings provide clinicians with a greater understanding of the spectrum of neuropsychological outcomes of pediatric CA survivors and the complex relationship between standardized caregiver-reported functional outcome measures incorporated in clinical trials and performance-based neuropsychological assessments.
Model intercomparison studies in the climate and Earth sciences communities have been crucial to building credibility and coherence for future projections. They have quantified variability among ...models, spurred model development, contrasted within- and among-model uncertainty, assessed model fits to historical data, and provided ensemble projections of future change under specified scenarios. Given the speed and magnitude of anthropogenic change in the marine environment and the consequent effects on food security, biodiversity, marine industries, and society, the time is ripe for similar comparisons among models of fisheries and marine ecosystems. Here, we describe the Fisheries and Marine Ecosystem Model Intercomparison Project protocol version 1.0 (Fish-MIP v1.0), part of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP), which is a cross-sectoral network of climate impact modellers. Given the complexity of the marine ecosystem, this class of models has substantial heterogeneity of purpose, scope, theoretical underpinning, processes considered, parameterizations, resolution (grain size), and spatial extent. This heterogeneity reflects the lack of a unified understanding of the marine ecosystem and implies that the assemblage of all models is more likely to include a greater number of relevant processes than any single model. The current Fish-MIP protocol is designed to allow these heterogeneous models to be forced with common Earth System Model (ESM) Coupled Model Intercomparison Project Phase 5 (CMIP5) outputs under prescribed scenarios for historic (from the 1950s) and future (to 2100) time periods; it will be adapted to CMIP phase 6 (CMIP6) in future iterations. It also describes a standardized set of outputs for each participating Fish-MIP model to produce. This enables the broad characterization of differences between and uncertainties within models and projections when assessing climate and fisheries impacts on marine ecosystems and the services they provide. The systematic generation, collation, and comparison of results from Fish-MIP will inform an understanding of the range of plausible changes in marine ecosystems and improve our capacity to define and convey the strengths and weaknesses of model-based advice on future states of marine ecosystems and fisheries. Ultimately, Fish-MIP represents a step towards bringing together the marine ecosystem modelling community to produce consistent ensemble medium- and long-term projections of marine ecosystems.
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