Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need for a ...highly efficient and scalable synthetic route to a complex molecular scaffold for diversification frequently inspires new methodological development or unique application of existing methods on structurally intricate systems. Additionally, synthetic planning with an aim toward late-stage diversification can provide access to otherwise unavailable compounds or facilitate preparation of complex molecules with diverse patterns of substitution around a shared carbon framework. For these reasons among others, programs dedicated to the diversification of natural product frameworks and other complex molecular scaffolds have been increasing in popularity, a trend likely to continue given their fruitfulness and breadth of impact. In this Perspective, we discuss our experience using late-stage diversification as a guiding principle for the synthesis of natural product analogs and reflect on the impact such efforts have on the future of complex molecule synthesis.
Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of ...disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports ...murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ-organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies.
A technology that simultaneously records membrane potential from multiple neurons in behaving animals will have a transformative effect on neuroscience research
. Genetically encoded voltage ...indicators are a promising tool for these purposes; however, these have so far been limited to single-cell recordings with a marginal signal-to-noise ratio in vivo
. Here we developed improved near-infrared voltage indicators, high-speed microscopes and targeted gene expression schemes that enabled simultaneous in vivo recordings of supra- and subthreshold voltage dynamics in multiple neurons in the hippocampus of behaving mice. The reporters revealed subcellular details of back-propagating action potentials and correlations in subthreshold voltage between multiple cells. In combination with stimulation using optogenetics, the reporters revealed changes in neuronal excitability that were dependent on the behavioural state, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behaviour. Fig. 1 PHOTOACTIVATED QUASAR3 (PAQUASAR3) REPORTS NEURONAL ACTIVITY IN VIVO.: a, Schematic of the paQuasAr3 construct. b, Photoactivation by blue light enhanced voltage signals excited by red light in cultured neurons that expressed paQuasAr3 (representative example of n = 4 cells). c, Model of the photocycle of paQuasAr3. d, Confocal images of sparsely expressed paQuasAr3 in brain slices. Scale bars, 50 μm. Representative images, experiments were repeated in n = 3 mice. e, Simultaneous fluorescence and patch-clamp recordings from a neuron expressing paQuasAr3 in acute brain slice. Top, magnification of boxed regions. Schematic shows brain slice, patch pipette and microscope objective. f, Simultaneous fluorescence and patch-clamp recordings of inhibitory post synaptic potentials in an L2-3 neuron induced by electrical stimulation of L5-6 in acute slice. g, Normalized change in fluorescence (ΔF/F) and SNR of optically recorded post-synaptic potentials (PSPs) as a function of the amplitude of the post-synaptic potentials. The voltage sensitivity was ΔF/F = 40 ± 1.7% per 100 mV. The SNR was 0.93 ± 0.07 per 1 mV in a 1-kHz bandwidth (n = 42 post-synaptic potentials from 5 cells, data are mean ± s.d.). Schematic shows brain slice, patch pipette, field stimulation electrodes and microscope objective. h, Optical measurements of paQuasAr3 fluorescence in the CA1 region of the hippocampus (top) and glomerular layer of the olfactory bulb (bottom) of anaesthetized mice (representative traces from n = 7 CA1 cells and n = 13 olfactory bulb cells, n = 3 mice). Schematics show microscope objective and the imaged brain region. i, STA fluorescence from 88 spikes in a CA1 oriens neuron. j, Frames from the STA video showing the delay in the back-propagating action potential in the dendrites relative to the soma. k, Sub-Nyquist fitting of the action potential delay and width shows electrical compartmentalization in the dendrites. Experiments in k-m were repeated in n = 2 cells from n = 2 mice.
Pectus excavatum is the most common chest wall skeletal deformity. Although commonly evaluated in adolescence, its prevalence in adults is unknown.
Radiographic indices of chest wall shape were ...analyzed for participants of the first (n = 2687) and second (n = 1780) phases of the population-based Dallas Heart Study and compared to clinical cases of pectus (n = 297). Thoracic computed tomography imaging studies were examined to calculate the Haller index, a measure of thoracic axial shape, and the Correction index, which quantitates the posterior displacement of the sternum relative to the ribs. At the level of the superior xiphoid, 0.5%, 5% and 0.4% of adult Dallas Heart Study subjects have evidence of pectus excavatum using thresholds of Haller index >3.25, Correction index >10%, or both, respectively. Radiographic measures of pectus are more common in females than males and there is a greater prevalence of pectus in women than men. In the general population, the Haller and Correction indices are associated with height and weight, independent of age, gender, and ethnicity. Repeat imaging of a subset of subjects (n = 992) demonstrated decreases in the mean Haller and Correction indices over seven years, suggesting change to a more circular axial thorax, with less sternal depression, over time.
To our knowledge, this is the first study estimating the prevalence of pectus in an unselected adult population. Despite the higher reported prevalence of pectus cases in adolescent boys, this study demonstrates a higher prevalence of radiographic indices of pectus in adult females.
A new strategy for the functionalization of sterically hindered terminal olefins is reported. Alkenes bearing quaternary carbons at the allylic or homoallylic position are readily oxidized to the ...corresponding aldehydes by palladium/copper/nitrite catalysis. A broad range of functional groups including esters, nitriles, silyl ethers, vinylogous esters, ketones, lactones, and β-ketoesters are tolerated under the reaction conditions. The crude aldehyde products can be transformed further, enabling direct conversion of hindered terminal alkenes to various other synthetically useful functional groups, resulting in formal anti-Markovnikov hydroamination, among other transformations.
The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule ...cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout KO) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.
► Investigated the game playing motivation using Self-Determination Theory. ► Examined the effects of competition upon intrinsic motivation in exergame context. ► Competition was tested both as a ...contextual and an individual trait. ► Competition provides positive experiences to competitive individuals. ► Competition factors do not benefit individuals who are less competitive.
This study examined the role of competition in exercise video games to promote intrinsic motivation for exercise. The experiment was a 2 (Competitive exercise context: Competition vs. No competition)×2 (Individual competitiveness: High vs. Low) between-subjects design. The results showed significant interaction effects of the independent variables on intrinsic motivation, mood, and evaluation of the exergame. That is, the competitive context provided positive exergame experiences to competitive individuals, whereas it had detrimental effects for less competitive participants. Implications and future directions are discussed.
To biomechanically characterize superior capsule reconstruction (SCR) using fascia lata allograft, double-layer dermal allograft, and single-layer dermal allograft for a clinically relevant massive ...irreparable rotator cuff tear involving the entire supraspinatus and 50% of the infraspinatus tendons.
Eight cadaveric specimens were tested in 0°, 30°, and 60° abduction for (1) intact, (2) massive rotator cuff tear, (3) SCR using fascia lata, (4) SCR using double-layer dermis, and (5) SCR using single-layer dermis. Superior translation and subacromial contact pressure were measured. Statistical analysis was conducted using repeated measures ANOVA or paired t test with P < .05.
Massive rotator cuff tear significantly increased superior translation of the humeral head at all abduction angles (P < .05). At 0° abduction, all SCR conditions significantly decreased superior translation compared with the massive tear but did not restore translation (P < .05) to intact. Fascia lata and double-layer dermis SCR restored superior translation to intact at 30° and 60° of abduction, but single-layer dermis did not. Subacromial contact pressure at 0° of abduction significantly decreased with SCR with fascia lata and double-layer dermis compared with tear. At 30°, all SCR conditions significantly decreased subacromial contact pressure. Single-layer dermis graft thickness significantly decreased more than fascia lata during testing (P = .02).
For SCR tensioned at 20° glenohumeral abduction, all 3 graft types may restore superior translation and subacromial contact pressure depending on the glenohumeral abduction angle; fascia lata and double-layer dermis may be more effective than single-layer dermis.
If a dermal graft is to be used for SCR, consideration should be given to doubling the graft for increased thickness and better restorative biomechanical properties, which may improve clinical outcomes following SCR.
We present Stellar Population Interface for Stellar Evolution and Atmospheres (SPISEA), an open-source Python package that simulates simple stellar populations. The strength of SPISEA is its modular ...interface which offers the user control of 13 input properties including (but not limited to) the initial mass function, stellar multiplicity, extinction law, and the metallicity-dependent stellar evolution and atmosphere model grids used. The user also has control over the initial-final mass relation in order to produce compact stellar remnants (black holes, neutron stars, and white dwarfs). We demonstrate several outputs produced by the code, including color-magnitude diagrams, HR-diagrams, luminosity functions, and mass functions. SPISEA is object-oriented and extensible, and we welcome contributions from the community. The code and documentation are available on GitHub (https://github.com/astropy/SPISEA) and ReadtheDocs (https://spisea.readthedocs.io/en/latest/), respectively.
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