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Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases
Abstract To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1×10−8), and CHEK2 at the suggestive threshold (P < 2.6×10−6). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75–3.83], P = 1.35×10−6), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07–0.25], P = 4.67×10−10), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.
AI-based approach to dissect the variability of mouse stem cell-derived embryo models
TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity
Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability
Abstract The ability to control the activity of kinases spatially and temporally is essential to elucidate the role of signalling pathways in development and physiology. Progress in this direction has been hampered by the lack of tools to manipulate kinase activity in a highly controlled manner in vivo. Here we report a strategy to modify BI2536, the well characterized inhibitor of the conserved and essential mitotic kinase Polo-like kinase 1 (Plk1). We introduce the same coumarin photolabile protecting group (PPG) at two positions of the inhibitor. At one position, the coumarin prevents the interaction with Plk1, at the second it masks an added carboxylic acid, important for cellular retention. Exposure to light results in removal of both PPGs, leading to the activation of the inhibitor and its trapping inside cells. We demonstrate the efficacy of the caged inhibitor in three-dimensional spheroid cultures: by uncaging it with a single light pulse, we can inhibit Plk1 and arrest cell division, a highly dynamic process, with spatio-temporal control. Our design can be applied to other small molecules, providing a solution to control their activity in living cells with unprecedented precision.
Hemiphosphoindigos as a platform for chiroptical or water soluble photoswitching
Abstract Photoswitches are important molecular tools to precisely control the behavior of matter by using light irradiation. They have found application in virtually all applied chemical fields from chemical biology to material sciences. However, great challenges remain in advanced property design including tailored chiroptical responses or water solubility. Here, hemiphosphoindigo (HPI) photoswitches are presented as capable phosphorus-based photoswitches and a distinct addition to the established indigoid chromophore family. Phosphinate is embedded in the core indigoid chromophore and the resulting optimized photoswitches display high thermal stabilities, excellent fatigue resistance and high isomer enrichment. A series of planar, twisted and heterocyclic HPIs are investigated to probe design strategies for advantageous photophysical properties. The phosphinate provides a platform for easily accessible, water-soluble photoswitches, especially interesting for biological applications. Its chiral nature further allows light-induced modulation of chiroptical properties. HPIs therefore open up a distinct structural space for photoswitch generation and advanced light-responsive applications.
Single-cell imaging reveals efficient nutrient uptake and growth of microalgae darkening the Greenland Ice Sheet
Abstract Blooms of dark pigmented microalgae accelerate glacier and ice sheet melting by reducing the surface albedo. However, the role of nutrient availability in regulating algal growth on the ice remains poorly understood. Here, we investigate glacier ice algae on the Greenland Ice Sheet, providing single-cell measurements of carbon:nitrogen:phosphorus (C:N:P) ratios and assimilation rates of dissolved inorganic carbon (DIC), ammonium and nitrate following nutrient amendments. The single-cell analyses reveal high C:N and C:P atomic ratios in algal biomass as well as intracellular P storage. DIC assimilation rates are not enhanced by ammonium, nitrate, or phosphate addition. Our combined results demonstrate that glacier ice algae can optimise nutrient uptake, facilitating the potential colonization of newly exposed bare ice surfaces without the need for additional nutrient inputs. This adaptive strategy is particularly important given accelerated climate warming and the expansion of melt areas on the Greenland Ice Sheet.
Molecular Self-Gating Inside a Zeolite Catalyst
Tip carbon encapsulation customizes cationic enrichment and valence stabilization for low K+ acidic CO2 electroreduction
Abstract Acidic electrochemical CO2 conversion is a promising alternative to overcome the low CO2 utilization. However, over-reliance on highly concentrated K+ to inhibit the hydrogen evolution reaction also causes (bi)carbonate precipitation to interfere with catalytic performance. In this work, under the screening and guidance of computational simulations, we present a carbon coated tip-like In2O3 electrocatalyst for stable and efficient acidic CO2 conversion to synthesize formic acid (HCOOH) with low K+ concentration. The carbon layer protects the oxidized In species with higher intrinsic activity from reductive corrosion, and also peripherally formulates a tip-induced electric field to regulate the adverse H+ attraction and desirable K+ enrichment. In an acidic electrolyte at pH 0.94, only 0.1 M low K+ is required to achieve a Faradaic efficiency (FE) of 98.9% at 300 mA cm−2 for HCOOH and a long-time stability of over100 h. By up-scaling the electrode into a 25 cm2 electrolyzer setup, a total current of 7 A is recorded to sustain a durable HCOOH production of 291.6 mmol L−1 h−1.
A fully conjugated meso-boron-substituted porphyrinoid combining Lewis acidity with redox-switchable aromaticity
Abstract The structural motif of porphyrin is relevant for many essential biological processes and has emerged as a versatile component of functional materials. Here, we introduce a thiophene-based porphyrinogen having electron-deficient boron atoms in all four meso-positions. Its fully π-conjugated backbone exhibits effectively concealed antiaromaticity, with locally confined aromaticity to the thiophene units. The macrocycle readily binds fluoride ions, signaled by changes in its photophysical characteristics. Global aromaticity is switched on via facile consecutive (electro)chemical one-electron reductions to give the radical anion and the dianion, the potassium salts both of which were isolated and characterized by single-crystal X-ray diffraction. The bowl-shaped dianion constitutes a tetrathiophene-based porphyrinoid with a metal cation in its coordination sphere. This 18-π-electron macrocycle shows absorption features typical of porphyrins, while its low-energy Q bands are unusually intense in relation to the Soret bands. In addition, it displays fluorescence emission in the near-infrared (NIR) spectral region.
Minimized optical/electrical energy loss for 25.1% Monolithic perovskite/organic tandem solar cells
Alternatively spliced NFKB1 transcripts enriched in Andean Aymara modulate inflammation, HIF and hemoglobin
Abstract The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts correlated with both transcripts and protein levels of inflammatory and HIF-regulated genes, including hemoglobin. While overexpression of the AS-NFKB1 variant led to increased expression of inflammatory and HIF-targeted genes; under inflammatory stress, NF-kB protein translocation to the nucleus was attenuated, resulting in reduced expression of these genes. Our study reveals AS-NFKB1 splicing events correlating with increased hemoglobin in Aymara and their possible protective mechanisms against excessive inflammation.
Single-molecule junctions map the interplay between electrons and chirality
<i>In Crystallo</i> Wolff Rearrangement of a Metalated Diazoester: Structural Confirmation of the Singlet Carbene Wolff-Intermediate
Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development
Streamlining Sulfated Oligosaccharide and Glycan Synthesis with Engineered Mutant 6-SulfoGlcNAcases
Parafermions in moiré minibands
Abstract Moiré materials provide a remarkably tunable platform for topological and strongly correlated quantum phases of matter. Very recently, the first Abelian fractional Chern insulators (FCIs) at zero magnetic field have been experimentally demonstrated, and it has been theoretically predicted that non-Abelian states with Majorana fermion excitations may be realized in the nearly dispersionless minibands of these systems. Here, we provide telltale evidence based on many-body exact diagonalization for the even more exotic possibility of moiré-based non-Abelian FCIs exhibiting Fibonacci parafermion excitations. In particular, we obtain low-energy quantum numbers, spectral flow, many-body Chern numbers, and entanglement spectra consistent with the $${{\mathbb{Z}}}_{3}$$ Z 3 Read–Rezayi parafermion phase in an exemplary moiré system with tunable quantum geometry. Our results hint towards the robustness of moiré-based parafermions and encourage the pursuit in moiré systems of these non-Abelian quasiparticles that are superior candidates for topological quantum computing.