Nature Communications最新文献

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.

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 4^th or 5^th 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.

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.

Influenced by non-stationary factors such as brain states and behavior, neurons exhibit substantial response variability even to identical stimuli. However, it remains unclear how their relative impact on neuronal variability evolves over time. To address this question, we designed an encoding model conditioned on latent states to partition variability in the mouse visual cortex across internal brain dynamics, behavior, and external visual stimulus. Applying a hidden Markov model to local field potentials, we consistently identified three distinct oscillation states, each with a unique variability profile. Regression models within each state revealed a dynamic composition of factors influencing spiking variability, with the dominant factor switching within seconds. The state-conditioned regression model uncovered extensive diversity in source contributions across units, varying in accordance with anatomical hierarchy and internal state. This heterogeneity in encoding underscores the importance of partitioning variability over time, particularly when considering the influence of non-stationary factors on sensory processing.

BK channels are large-conductance calcium (Ca²⁺)-activated potassium channels crucial for neuronal excitability, muscle contraction, and neurotransmitter release. The pore-forming (α) subunits co-assemble with auxiliary (β and γ) subunits that modulate their function. Previous studies demonstrated that the N-termini of β2-subunits can inactivate BK channels, but with no structural correlate. Here, we investigate BK β2-subunit inactivation using cryo-electron microscopy, electrophysiology and molecular dynamics simulations. We find that the β2 N-terminus occludes the pore only in the Ca²⁺-bound open state, via a ball-and-chain mechanism. The first three hydrophobic residues of β2 are crucial for occlusion, while the remainder of the N-terminus remains flexible. Neither the closed channel conformation obtained in the absence of Ca²⁺ nor an intermediate conformation found in the presence of Ca²⁺ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore.

The interplay of electrons with a chiral medium has a diverse impact across science and technology, influencing drug separation, chemical reactions, and electronic transport^1-30. In particular, electron-chirality interactions can significantly affect charge and spin transport in chiral conductors, making them highly appealing for spintronics. However, an atomistic mapping of different electron-chirality interactions remains elusive. Here, we find that helicene-based single-molecule junctions behave as a combined magnetic-diode and spin-valve device. This dual-functionality enables the identification of an atomic-scale coexistence of different electron-chirality interactions: the magnetic-diode behavior is attributed to an interaction between electron’s angular momentum in a chiral medium and magnetic fields, whereas the spin-valve functionality is ascribed to an interaction between the electron’s spin and a chiral medium. This work uncovers the coexistence of electron-chirality interactions at the atomic-scale, identifies their distinct properties, and demonstrates how integrating their functionalities can broaden of the available methods for spintronics.

Recent advances in stem cell-derived embryo models have transformed developmental biology, offering insights into embryogenesis without the constraints of natural embryos. However, variability in their development challenges research standardization. To address this, we use deep learning to enhance the reproducibility of selecting stem cell-derived embryo models. Through live imaging and AI-based models, we classify 900 mouse post-implantation stem cell-derived embryo-like structures (ETiX-embryos) into normal and abnormal categories. Our best-performing model achieves 88% accuracy at 90 h post-cell seeding and 65% accuracy at the initial cell-seeding stage, forecasting developmental trajectories. Our analysis reveals that normally developed ETiX-embryos have higher cell counts and distinct morphological features such as larger size and more compact shape. Perturbation experiments increasing initial cell numbers further supported this finding by improving normal development outcomes. This study demonstrates deep learning’s utility in improving embryo model selection and reveals critical features of ETiX-embryo self-organization, advancing consistency in this evolving field.

Skeletal muscle is a heterogenous tissue comprised primarily of myofibers, commonly classified into three fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X). However, heterogeneity between and within traditional fiber types remains underexplored. We applied transcriptomic and proteomic workflows to 1050 and 1038 single myofibers from human vastus lateralis, respectively. Proteomics was conducted in males, while transcriptomics included ten males and two females. We identify metabolic, ribosomal, and cell junction proteins, in addition to myosin heavy chain isoforms, as sources of multi-dimensional variation between myofibers. Furthermore, whilst slow and fast fiber clusters are identified, our data suggests that type 2X fibers are not phenotypically distinct to other fast fibers. Moreover, myosin heavy chain-based classifications do not adequately describe the phenotype of myofibers in nemaline myopathy. Overall, our data indicates that myofiber heterogeneity is multi-dimensional with sources of variation beyond myosin heavy chain isoforms.

Recent studies have highlighted the crucial role of microglia (MG) and their interactions with the gut microbiome in post-stroke neuroinflammation. The activation of immunoregulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, is influenced by a dynamic balance of ligands derived from both the host and microbiota. This study aimed to investigate the association between stroke-induced dysbiosis and the resultant imbalance in AHR ligand sources (loss of microbiota-derived [indole-based] and increase of host-derived [kynurenine-based]) after stroke. Microbiota-derived AHR ligands decreased in human plasma and remained low for days following an ischemic stroke highlighting the translational significance. Transient-middle-cerebral-artery-occlusion was performed in aged wild-type and germ-free male mice. MG-AHR expression and activity increased in both in vivo and ex vivo stroke models. Germ-free mice showed altered neuroinflammation and antigen presentation while aged mice showed reduced infarct volume and neurological deficits following treatment with microbiota-derived AHR ligands after stroke. Restoring a balanced pool of host- and microbiota-derived AHR ligands may be beneficial after stroke and may represent a therapeutic target.

The tumor-suppressive function of p53 is frequently disrupted by mutations in cancers. Missense mutant p53 (mutp53) protein often stabilizes and accumulates to high levels in cancers to promote tumorigenesis through the gain-of-function (GOF) mechanism. Currently, the mechanism of mutp53 accumulation and GOF is incompletely understood. Here, we identify the lipogenic enzyme FASN as an important regulator of mutp53 accumulation and GOF. FASN interacts with mutp53 to enhance mutp53 palmitoylation, which inhibits mutp53 ubiquitination to promote mutp53 accumulation and GOF. Blocking FASN genetically or by small-molecule inhibitors suppresses mutp53 palmitoylation to inhibit mutp53 accumulation, which in turn inhibits the growth of mutp53 tumors in orthotopic and subcutaneous xenograft tumor models and transgenic mice, as well as the growth of human tumor organoids carrying mutp53. Our results reveal that mutp53 palmitoylation is an important mechanism underlying mutp53 accumulation and GOF, and targeting FASN is a potential therapeutic strategy for cancers carrying mutp53.