Ottevalentin0660

In this issue of Structure,Shang and Kojetin (2021) present insights into the binding mechanism of artificial agonists to the PPARγ nuclear receptor. These data support a two-step model with induced fit and conformational selection aspects. This mechanism may exist in related receptors, providing new opportunities for drug development.Haplotype phasing is the estimation of haplotypes from genotype data. We present a fast, accurate, and memory-efficient haplotype phasing method that scales to large-scale SNP array and sequence data. The method uses marker windowing and composite reference haplotypes to reduce memory usage and computation time. It incorporates a progressive phasing algorithm that identifies confidently phased heterozygotes in each iteration and fixes the phase of these heterozygotes in subsequent iterations. For data with many low-frequency variants, such as whole-genome sequence data, the method employs a two-stage phasing algorithm that phases high-frequency markers via progressive phasing in the first stage and phases low-frequency markers via genotype imputation in the second stage. This haplotype phasing method is implemented in the open-source Beagle 5.2 software package. We compare Beagle 5.2 and SHAPEIT 4.2.1 by using expanding subsets of 485,301 UK Biobank samples and 38,387 TOPMed samples. Both methods have very similar accuracy and computation time for UK Biobank SNP array data. However, for TOPMed sequence data, Beagle is more than 20 times faster than SHAPEIT, achieves similar accuracy, and scales to larger sample sizes.Metabolic dysfunction is becoming a predominant risk for the development of many comorbidities. Ischemic heart disease (IHD) still imposes the highest disease burden among all cardiovascular diseases worldwide. However, the contributions of metabolic risk factors to IHD over time have not been fully characterized. Here, we analyzed the global disease burden of IHD and 15 associated general risk factors from 1990 to 2019 by applying the methodology framework of the Global Burden of Disease Study. We found that the global death cases due to IHD increased steadily during that time frame, while the mortality rate gradually declined. Notably, metabolic risk factors have become the leading driver of IHD, which also largely contributed to the majority of IHD-related deaths shifting from developed countries to developing countries. These findings suggest an urgent need to implement effective measures to control metabolic risk factors to prevent further increases in IHD-related deaths.Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.Higher-order projections to sensory cortical areas converge on layer 1 (L1), the primary site for integration of top-down information via the apical dendrites of pyramidal neurons and L1 GABAergic interneurons. Here we investigated the contribution of early thalamic inputs onto L1 interneurons for establishment of top-down connectivity in the primary visual cortex. We find that bottom-up thalamic inputs predominate during L1 development and preferentially target neurogliaform cells. We show that these projections are critical for the subsequent strengthening of top-down inputs from the anterior cingulate cortex onto L1 neurogliaform cells. Sensory deprivation or selective removal of thalamic afferents blocked this phenomenon. Although early activation of the anterior cingulate cortex resulted in premature strengthening of these top-down afferents, this was dependent on thalamic inputs. Our results demonstrate that proper establishment of top-down connectivity in the visual cortex depends critically on bottom-up inputs from the thalamus during postnatal development.Over the course of the last decade, the biopharmaceutical industry has slowly adopted human inducible pluripotent stem cell (hiPSC) technology to enable the development of humanized model systems to test new therapeutic molecules and drug modalities. The adoption of hiPSC-based models by the industry has increased appreciably in the past 3-5 years. This increase has paralleled the explosion in availability of high-quality human genetic data to mine for new drug targets and the emergence of human-specific therapeutic modalities.In this issue of Cell Stem Cell, Tallapragada et al. (2021) present an intestinal organoid culture system for high-throughput live imaging to investigate niche-independent mechanisms of crypt fission. They find that Piezo activity downregulates Lgr5 expression in stretched epithelial cells within inflated organoids, which form multiple new crypts upon collapse.Despite being a biologically fundamental question, the precise timing of lineage specification during human preimplantation development remains elusive. In this issue of Cell Stem Cell, Meistermann et al. (2021) refine our view through time-lapse embryo staging and single-cell sequencing and challenge the concept of a human inner cell mass.Epidermal stem cells display remarkable capacities to restore the barrier upon skin injury. In this issue of Cell Stem Cell, Huang et al. (2021) use innovative high-resolution intravital imaging to identify a vital function of sensory nerves in regulating a subset of epidermal stem cells for wound repair.The use of wastewater-grown microalgae has the potential to reduce the cost of algae-derived biofuels while simultaneously advancing nutrient recovery at water resource recovery facilities (WRRFs). However, a significant barrier has been the low yield and high protein content of phototrophic biomass. Here, we examine the use of solids residence time (SRT) as a selective pressure in driving biochemical composition, yield, biofuel production, and WRRF nutrient management cost. We cultivated mixed phototrophic communities in controlled, laboratory-scale photobioreactors on the local WRRF secondary effluent to link SRT with biochemical composition and techno-economic analysis to yield insights into biomass composition and downstream processing effects on minimum fuel selling price. SRT significantly impacted biochemical composition, with total and dynamic carbohydrates the highest at low SRT (total carbohydrates being 0.60 and 0.32 mg-carbohydrate·mg-protein-1 at SRT 5 and 15 days, respectively). However, there were distinct differences between extant, steady-state performance and intrinsic potential, and longer SRT communities were able to accumulate significant fractions (51% on an ash-free dry weight basis, AFDW %) of carbohydrate reserves under nutrient starvation. Overall, hydrothermal liquefaction (HTL) was found to be more suitable than lipid extraction for hydrotreating (LEH) and combined algal processing (CAP) for conversion of biomass to fuels, but LEH and CAP became more competitive when intrinsic carbon storage potential was realized. The results suggest that the use of algae for nutrient recovery could reduce the nutrient management cost at WRRFs through revenue from algal biofuels, with HTL resulting in a net revenue.Reaction barriers are key to our understanding of chemical reactivity and catalysis. Certain reactions are so seminal in chemistry that countless variants, with or without catalysts, have been studied, and their barriers have been computed or measured experimentally. This wealth of data represents a perfect opportunity to leverage machine learning models, which could quickly predict barriers without explicit calculations or measurement. Here, we show that the topological descriptors of the quantum mechanical charge density in the reactant state constitute a set that is both rigorous and continuous and can be used effectively for the prediction of reaction barrier energies to a high degree of accuracy. We demonstrate this on the Diels-Alder reaction, highly important in biology and medicinal chemistry, and as such, studied extensively. This reaction exhibits a range of barriers as large as 270 kJ/mol. While we trained our single-objective supervised (labeled) regression algorithms on simpler Diels-Alder reactions in solution, they predict reaction barriers also in significantly more complicated contexts, such a Diels-Alder reaction catalyzed by an artificial enzyme and its evolved variants, in agreement with experimental changes in kcat. We expect this tool to apply broadly to a variety of reactions in solution or in the presence of a catalyst, for screening and circumventing heavily involved computations or experiments.The LiCoO2 cathode undergoes undesirable electrochemical performance when cycled with a high cut-off voltage (≥4.5 V versus Li/Li+). The unstable interface with poor kinetics is one of the main contributors to the performance failure. Hence, a hybrid Li-ion conductor (Li1.5Al0.5Ge1.5P3O12) and electron conductor (Al-doped ZnO) coating layer was built on the LiCoO2 surface. Characterization studies prove that a thick and conductive layer is homogeneously covered on LiCoO2 particles. The coating layer can not only enhance the interfacial ionic and electronic transport kinetics but also act as a protective layer to suppress the side reactions between the cathode and electrolyte. Adenosine Cyclophosphate The modified LiCoO2 (HC-LCO) achieves an excellent cycling stability (77.1% capacity retention after 350 cycles at 1C) and rate capability (139.8 mAh g-1 at 10C) at 3.0-4.6 V. Investigations show that the protective layer can inhibit the particle cracks and Co dissolution and stabilize the cathode electrolyte interface (CEI). Furthermore, the irreversible phase transformation is still observed on the HC-LCO surface, indicating the phase transformation of the LiCoO2 surface may not be the main factor for fast performance failure. This work provides new insight of interfacial design for cathodes operating with a high cut-off voltage.Three-dimensional cell cultures are of growing importance in biochemical research as they represent tissue features more accurately than standard two-dimensional systems, but to investigate these challenging new models an adaptation of established analytical techniques is required. Spatially resolved data for living organoids are needed to gain insight into transport processes and biochemical characteristics of domains with different nutrient supply and waste product removal. Within this work, we present an NMR-based approach to obtain dynamically radial metabolite profiles for cell spheroids, one of the most frequently used 3D models. Our approach combines an easy to reproduce custom-made measurement design, maintaining physiological conditions without inhibition of the NMR experiment, with spatially selective NMR pulse sequences. To overcome the inherently low sensitivity of NMR spectroscopy we excited slices instead of smaller cube-like voxels in combination with an efficient interleaved measurement approach and employed a commercially available cryogenic NMR probe.