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  1. SUMMARY

    Gravity surveys constitute an important method for investigating the Earth's interior based on density contrasts related to Earth material differentials. Because lithology depends on the environment and the period of formation, there are generally clear boundaries between rocks with different lithologies. Inversions with convex functions for approximating the L0 norm are used to detect boundaries in reconstructed models. Optimizations can easily be found because of the convex transformations; however, the volume of the reconstructed model depends on the weighting parameter and the density constraint rather than the model sparsity. To determine and adapt the modelling size, a novel non-convex framework for gravity inversion is proposed. The proposed optimization aims to directly reduce the L0 norm of the density matrix. An improved iterative hard thresholding algorithm is developed to linearly reduce the L0 penalty during the inner iteration. Accordingly, it is possible to determine the modelling scale during the iteration and achieve an expected scale for the reconstructed model. Both simple and complex model experiments demonstrate that the proposed method efficiently reconstructs models. In addition, granites formed during the Yanshanian and Indosinian periods in the Nanling region, China, are reconstructed according to the modelling size evaluated in agreement with the magnetotelluric profile and density statistics of rock samples. The known ores occur at the contact zones between the sedimentary rocks and the reconstructed Yanshanian granites. The ore-forming bodies, periods, and processes are identified, providing guidance for further deep resource exploration in the study area.

     
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  2. ABSTRACT

    Characterizing the structural properties of galaxies in high-redshift protoclusters is key to our understanding of the environmental effects on galaxy evolution in the early stages of galaxy and structure formation. In this study, we assess the structural properties of 85 and 87 Hα emission-line candidates (HAEs) in the densest regions of two massive protoclusters, BOSS1244 and BOSS1542, respectively, using the Hubble Space Telescope (HST) H-band imaging data. Our results show a true pair fraction of 22 ± 5 (33 ± 6) per cent in BOSS1244 (BOSS1542), which yields a merger rate of 0.41 ± 0.09 (0.52 ± 0.04) Gyr−1 for massive HAEs with log (M*/M⊙) ≥ 10.3. This rate is 1.8 (2.8) times higher than that of the general fields at the same epoch. Our sample of HAEs exhibits half-light radii and Sérsic indices that cover a broader range than field star-forming galaxies. Additionally, about 15 per cent of the HAEs are as compact as the most massive (log (M*/M⊙) ≳ 11) spheroid-dominated population. These results suggest that the high galaxy density and cold dynamical state (i.e. velocity dispersion of <400 km s−1) are key factors that drive galaxy mergers and promote structural evolution in the two protoclusters. Our findings also indicate that both the local environment (on group scales) and the global environment play essential roles in shaping galaxy morphologies in protoclusters. This is evident in the systematic differences observed in the structural properties of galaxies between BOSS1244 and BOSS1542.

     
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  3. Abstract Background

    Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes.

    Methods

    By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes.

    Results

    We identified ~80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of ~10K target genes (i.e., “trans-eGenes”). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL’s target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL’s target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci).

    Conclusions

    We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.

     
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  5. Tumorigenic risk of undifferentiated human induced pluripotent stem cells (iPSCs), being a major obstacle for clinical application of iPSCs, requires novel approaches for selectively eliminating undifferentiated iPSCs. Here, we show that an l-phosphopentapeptide, upon the dephosphorylation catalyzed by alkaline phosphatase (ALP) overexpressed by iPSCs, rapidly forms intranuclear peptide assemblies made of alpha-helices to selectively kill iPSCs. The phosphopentapeptide, consisting of four l-leucine residues and a C-terminal l-phosphotyrosine, self-assembles to form micelles/nanoparticles, which transform into peptide nanofibers/nanoribbons after enzymatic dephosphorylation removes the phosphate group from the l-phosphotyrosine. The concentration of ALP and incubation time dictates the morphology of the peptide assemblies. Circular dichroism and FTIR indicate that the l-pentapeptide in the assemblies contains a mixture of an alpha-helix and aggregated strands. Incubating the l-phosphopentapeptide with human iPSCs results in rapid killing of the iPSCs (=<2 h) due to the significant accumulation of the peptide assemblies in the nuclei of iPSCs. The phosphopentapeptide is innocuous to normal cells (e.g., HEK293 and hematopoietic progenitor cell (HPC)) because normal cells hardly overexpress ALP. Inhibiting ALP, mutating the l-phosphotyrosine from the C-terminal to the middle of the phosphopentapeptides, or replacing l-leucine to d-leucine in the phosphopentapeptide abolishes the intranuclear assemblies of the pentapeptides. Treating the l-phosphopentapeptide with cell lysate of normal cells (e.g., HS-5) confirms the proteolysis of the l-pentapeptide. This work, as the first case of intranuclear assemblies of peptides, not only illustrates the application of enzymatic noncovalent synthesis for selectively targeting nuclei of cells but also may lead to a new way to eliminate other pathological cells that express a high level of certain enzymes. 
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  6. Alkaline phosphatase (ALP) enables intracellular targeting by peptide assemblies, but how the ALP substrates enter cells remains elusive. Here we show that nanoscale phosphopeptide assemblies cluster ALP to enable caveolae-mediated endocytosis (CME) and endosomal escape. Specifically, fluorescent phosphopeptides undergo enzyme-catalyzed self-assembly to form nanofibers. Live cell imaging unveils that phosphopeptides nanoparticles, coincubated with HEK293 cells overexpressing red fluorescent protein-tagged tissue-nonspecific ALP (TNAP-RFP), cluster TNAP-RFP in lipid rafts to enable CME. Further dephosphorylation of the phosphopeptides produces peptidic nanofibers for endosomal escape. Inhibiting TNAP, cleaving the membrane anchored TNAP, or disrupting lipid rafts abolishes the endocytosis. Decreasing the transformation to nanofibers prevents the endosomal escape. As the first study establishing a dynamic continuum of nanoscale assemblies for cellular uptake, this work illustrates an effective design for enzyme-responsive supramolecular therapeutics and provides mechanism insights for understanding the dynamics of cellular uptake of proteins or exogenous peptide aggregates. 
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