Communications Biology最新文献

Most of our knowledge of protein structure and function originates from experiments performed with purified proteins resuspended in dilute, buffered solutions. However, most proteins function in crowded intracellular environments with complex compositions. Significant efforts have been made to develop tools to study proteins in their native cellular settings. Among these tools, in-cell NMR spectroscopy has been the sole technique for characterizing proteins in the intracellular space of living cells at atomic resolution and physiological temperature. Nevertheless, due to technological constraints, in-cell NMR studies have been limited to asynchronous single-cell suspensions, precluding obtaining information on protein behavior in different cellular states. In this study, we present a methodology that allows for obtaining an atomically resolved NMR readout of protein structure and interactions in living human cells synchronized in specific cell cycle phases and within 3D models of human tissue. The described approach opens avenues for investigating how protein structure or drug recognition responds to cell-cell communication or changes in intracellular space composition during transitions among cell cycle phases.

The capacity of the brain to process input across temporal scales is exemplified in human narrative, which requires integration of information ranging from words, over sentences to long paragraphs. It has been shown that this processing is distributed in a hierarchy across multiple areas in the brain with areas close to the sensory cortex, processing on a faster time scale than areas in associative cortex. In this study we used reservoir computing with human derived connectivity to investigate the effect of the structural connectivity on time scales across brain regions during a narrative task paradigm. We systematically tested the effect of removal of selected fibre bundles (IFO, ILF, MLF, SLF I/II/III, UF, AF) on the processing time scales across brain regions. We show that long distance pathways such as the IFO provide a form of shortcut whereby input driven activation in the visual cortex can directly impact distant frontal areas. To validate our model we demonstrated significant correlation of our predicted time scale ordering with empirical results from the intact/scrambled narrative fMRI task paradigm. This study emphasizes structural connectivity's role in brain temporal processing hierarchies, providing a framework for future research on structure and neural dynamics across cognitive tasks.

A large number of SpCas9 orthologs has been computationally identified, but their genome editing potential remains largely unknown. In this study, a GFP-activation assay was used to screen a panel of 18 SpCas9 orthologs, ten of which demonstrated activity in human cells. Notably, these orthologs had a preference for purine-rich PAM sequences. Four of the tested orthologs displayed enhanced specificity compared to SpCas9. Of particular interest is SeqCas9, which recognizes a simple NNG PAM and displays activity and specificity comparable to SpCas9-HF1. In addition, SeqCas9 exhibits superior base editing efficiency compared to SpCas9-NG and SpCas9-NRRH at multiple endogenous loci. This research sheds light on the diversity of SpCas9 orthologs and their potential for specific and efficient genome editing, especially in cases involving base editing.

Plasmodium species replicate via schizogony, which involves asynchronous nuclear divisions followed by semi-synchronous segmentation and cytokinesis. Successful segmentation requires a double-membranous structure known as the inner membrane complex (IMC). Here we demonstrate that PfFBXO1 (PF3D7_0619700) is critical for both asexual segmentation and gametocyte maturation. In Toxoplasma gondii, the FBXO1 homolog, TgFBXO1, is essential for the development of the daughter cell scaffold and a component of the daughter cell IMC. We demonstrate PfFBXO1 forming a similar IMC initiation scaffold near the apical region of developing merozoites and unilaterally positioned in gametocytes of P. falciparum. While PfFBXO1 initially localizes to the apical region of dividing parasites, it displays an IMC-like localization as segmentation progresses. Similarly, PfFBXO1 localizes to the IMC region in gametocytes. Following inducible knockout of PfFBXO1, parasites undergo abnormal segmentation and karyokinesis, generating inviable daughters. PfFBXO1-deficient gametocytes are abnormally shaped and fail to fully mature. Proteomic analysis identified PfSKP1 as one of PfBXO1's stable interacting partners, while other major proteins included multiple IMC pellicle and membrane proteins. We hypothesize that PfFBXO1 is necessary for IMC biogenesis, chromosomal maintenance, vesicular transport, and ubiquitin-mediated translational regulation of proteins in both sexual and asexual stages of P. falciparum.

The F-type ATP synthase inhibitor bedaquiline (BDQ) is a potent inhibitor of mycobacterial growth and this inhibition cannot be rescued by fermentable carbon sources that would supply ATP by an alternative pathway (substrate level phosphorylation). To gain mechanistic insight into this phenomenon, we employed a metabolic engineering approach. We introduced into Mycobacterium smegmatis an alternative ATP production pathway by substrate-level phosphorylation, specifically through overexpression of trypanosomal acetate:succinate co-enzyme A (CoA) transferase (ASCT). Intriguingly, the overexpression of ASCT partially restored intracellular ATP levels and resulted in acquired tolerance to BDQ growth inhibition at low, but not high concentrations of BDQ. These results implicate intracellular ATP levels in modulating the growth inhibitory activity of BDQ at low concentrations. These findings shed light on the intricate interplay between BDQ and mycobacterial energy metabolism, while also providing a novel tool for the development of next-generation ATP synthase-specific inhibitors targeting mycobacteria.

Color vision is thought to play a key role in the evolution of animal coloration, while achromatic vision is rarely considered as a mechanism for species recognition. Here we test the hypothesis that brightness vision rather than color vision helps Adelpha fessonia butterflies identify potential mates while their co-mimetic wing coloration is indiscriminable to avian predators. We examine the trichromatic visual system of A. fessonia and characterize its photoreceptors using RNA-seq, eyeshine, epi-microspectrophotometry, and optophysiology. We model the discriminability of its wing color patches in relation to those of its co-mimic, A. basiloides, through A. fessonia and avian eyes. Visual modeling suggests that neither A. fessonia nor avian predators can readily distinguish the co-mimics' coloration using chromatic or achromatic vision under natural conditions. These results suggest that mimetic colors are well-matched to visual systems to maintain mimicry, and that mate avoidance between these two look-alike species relies on other cues.

Cyanides are highly toxic chemicals in several edible plants that threaten food safety and human health. A phenotypically distinct Yarrowia lipolytica strain that efficiently detoxifies multiple cyanogenic glycosides from edible plants was constructed using a family 1 glycosyl-hydrolase (GH1). The strain displayed higher growth rates and metabolic activities when exposed to high concentrations of cyanides than the wild-type. It overexpressed genes that promoted the binding of molecular oxygen to the cytochrome iv complex. The engineered strain repressed fatty acid production to optimize energy production and activated the cyanide-resistant respiratory (AOX) pathway to circumvent HCN toxicity and maintain cellular homeostasis. It upregulated ribosome biogenesis, the sec-dependent protein export pathway, and the sulfur relay system to facilitate the production and transmembrane efflux of the secreted GH1 hydrolase. It efficiently degraded linamarin, amygdalin, prunasin, and dhurrin in food plants including cassava, germinated sorghum and Apricot seeds. The strain produced high phospholipids to support new membrane production and could be a cost-effective source of single-cell phospholipids. The findings demonstrate that the strain is a robust, sustainable, and potentially efficient strain that could be used for industrial bioconversion of plant materials containing glycosylated toxicants into safe foods and animal feeds.

Methoxylated aromatic compounds, are abundant in subsurface ecosystems. Recently, it was discovered that Methermicoccus shengliensis can convert methoxylated aromatics to methane. Specifically, the MATE family transporters (MatE) and transduction-like protein (Tlp) were hypothesized to play a crucial role in substrate transport. However, their biological function and the transporting model remained unclear. To address this knowledge gap, we employed bacterial two-hybrid and structural model assays to investigate the interaction between Tlp and MatE. Our results revealed that Tlp senses 2-methoxybenzoate and interacts with MatE to facilitate substrate transport. Furthermore, we observed that the matE knock-out mutant significantly impaired the growth and methane production of M. shengliensis when using 2-methoxybenzoate as a substrate, highlighting the essential role of MatE in methoxydotrophic methanogenesis. Overall, our findings suggest that the MatE-Tlp system regulates substrate uptake and methane metabolism in M. shengliensis, providing new avenues for reducing global methane emissions caused by methanogens.

Oligodendrocytes are the myelinating cells within the central nervous system, but the mechanisms by which transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remain unclear. We introduce coTF-reg, an analytical framework that integrates scRNA-seq and scATAC-seq data to identify cooperative TFs co-regulating the target gene (TG). First, we identify co-binding TF pairs in the same oligodendrocyte-specific regulatory regions. Next, we train a deep learning model to predict each TG expression using the co-binding TFs' expressions. Shapley interaction scores reveal high interactions between co-binding TF pairs, such as SOX10-TCF12. Validation using oligodendrocyte eQTLs and their eGenes that are regulated by these cooperative TFs show potential regulatory roles for genetic variants. Experimental validation using ChIP-seq data confirms some cooperative TF pairs, such as SOX10-OLIG2. Prediction performance of our models is evaluated through holdout data and additional datasets, and an ablation study is also conducted. The results demonstrate stable and consistent performance.