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Pearl millet is an important cereal crop worldwide and shows superior heat tolerance. Here, we developed a graph-based pan-genome by assembling ten chromosomal genomes with one existing assembly adapted to different climates worldwide and captured 424,085 genomic structural variations (SVs). Comparative genomics and transcriptomics analyses revealed the expansion of the RWP-RK transcription factor family and the involvement of endoplasmic reticulum (ER)-related genes in heat tolerance. The overexpression of one RWP-RK gene led to enhanced plant heat tolerance and transactivated ER-related genes quickly, supporting the important roles of RWP-RK transcription factors and ER system in heat tolerance. Furthermore, we found that some SVs affected the gene expression associated with heat tolerance and SVs surrounding ER-related genes shaped adaptation to heat tolerance during domestication in the population. Our study provides a comprehensive genomic resource revealing insights into heat tolerance and laying a foundation for generating more robust crops under the changing climate.

Sex differences in Alzheimer's disease (AD) progression provide clues to pathogenesis and better patient management. We examined sex differences in emotional memory among AD patients, amnestic mild cognitive impairment (aMCI) patients, and healthy controls (HCs) as well as potential associations with altered regional cerebral blood flow (rCBF).The recognition memory task with emotional pictures was applied to evaluate enhancement of emotional memory (EEM) and 3D pseudo-continuous arterial spin labeling MRI was performed to measure the rCBF in 74 AD patients (41 females), 74 aMCI patients (45 females), and 74 HCs (43 females). Group differences in EEM were tested by two-way analysis of covariance (ANCOVA) with repeated measures. The main effects of clinical group and sex as well as group × sex interactions on rCBF were assessed by two-way ANCOVA. Correlation analyses were conducted to investigate associations between EEM and rCBF.With disease progression, EEM gradually disappeared. Among aMCI patients, females exhibited a greater index of recollection (Pr) for positive/high-arousal and negative/low-arousal pictures versus neutral pictures (P = 0.005, P = 0.003), while males exhibited a greater Pr for negative/high-arousal versus neutral pictures (P = 0.001). There were significant sex × group effects on rCBF in left inferior parietal, supramarginal, superior temporal and middle temporal gyri, and rCBF of left inferior parietal gyrus was correlated with Pr for positive/high-arousal pictures among female aMCI patients (r = 0.584, q = 0.005).Males and females exhibit distinct changes in EEM associated with altered rCBF, which should be considered in future neuroimaging studies.

Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenotype switching that occurs during the epithelial-to-mesenchymal transition (EMT). Although drug-induced epigenetic reprogramming is believed to alter the sensitivity of cancer cells to anticancer treatments, there is still much to learn about overcoming drug resistance. In this study, we used an in vitro model of ceritinib-resistant NSCLC and employed genome-wide DNA methylation analysis in combination with single-cell (sc) RNA-seq to identify cytidine deaminase (CDA), a pyrimidine salvage pathway enzyme, as a candidate drug target. CDA was hypomethylated and upregulated in ceritinib-resistant cells. CDA-overexpressing cells were rarely but definitively detected in the naïve cell population by scRNA-seq, and their abundance was increased in the acquired-resistance population. Knockdown of CDA had antiproliferative effects on resistant cells and reversed the EMT phenotype. Treatment with epigenome-related nucleosides such as 5-formyl-2′-deoxycytidine selectively ablated CDA-overexpressing resistant cells via accumulation of DNA damage. Collectively, our data suggest that targeting CDA metabolism using epigenome-related nucleosides represents a potential new therapeutic strategy for overcoming ALK inhibitor resistance in NSCLC.

This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

Direct electrochemical nitrate reduction reaction (NITRR) is a promising strategy to alleviate the unbalanced nitrogen cycle while achieving the electrosynthesis of ammonia. However, the restructuration of the high-activity Cu-based electrocatalysts in the NITRR process has hindered the identification of dynamical active sites and in-depth investigation of the catalytic mechanism. Herein, Cu species (single-atom, clusters, and nanoparticles) with tunable loading supported on N-doped TiO2/C are successfully manufactured with MOFs@CuPc precursors via the pre-anchor and post-pyrolysis strategy. Restructuration behavior among Cu species is co-dependent on the Cu loading and reaction potential, as evidenced by the advanced operando X-ray absorption spectroscopy, and there exists an incompletely reversible transformation of the restructured structure to the initial state. Notably, restructured CuN4&Cu4 deliver the high NH3 yield of 88.2 mmol h−1 gcata−1 and FE (~ 94.3%) at − 0.75 V, resulting from the optimal adsorption of NO3− as well as the rapid conversion of *NH2OH to *NH2 intermediates originated from the modulation of charge distribution and d-band center for Cu site. This work not only uncovers CuN4&Cu4 have the promising NITRR but also identifies the dynamic Cu species active sites that play a critical role in the efficient electrocatalytic reduction in nitrate to ammonia.

Acknowledgements: L.K. was supported by a Ph.D. Fellowship from the Boehringer Ingelheim Fonds. This work was supported by the MRC (UK; U105181010), a Wellcome Trust Investigator Award (223054/Z/21/Z) and a Wellcome Trust Collaborator Award (214344/A/18/Z)., Funder: Boehringer Ingelheim Fonds (Stiftung für medizinische Grundlagenforschung); doi: https://doi.org/10.13039/501100001645, TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn't prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.

Biocompostable poly (glycolic acid) (PGA) crystallizes slowly under fast cooling condition, leading to poor mechanical performance of the final products. In this work, a self-nucleation (SN) route was carried out to promote the crystallization of PGA by regulating only the thermal procedure without any extra nucleating agents. When self-nucleation temperature (Ts) decreased from 250 oC to 227 oC, the nuclei density was increased, and the non-isothermal crystallization temperature (Tc) of PGA was increased from 156 oC to 197 oC and the half-life time (t0.5) of isothermal crystallization at 207 oC was decreased by 89%. Consequently, the tensile strength and the elongation at break of the PGA were increased by 12% and 189%, respectively. According to the change of Tc as a function of Ts, a three-stage temperature domain map (Domain I, II and III) was protracted and the viscoelastic behavior of the self-nucleation melt and the homogeneous melt was studied. The results indicated that interaction among PGA chains was remained in Domain IIb, which can act as pre-ordered structure to accelerate the overall crystallization rate. This work utilizes a simple and effective SN method to regulate the crystallization behavior and the mechanical properties of PGA, which may broaden the application range of resulting materials.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently identified autoimmune disorder with heterogeneous neurological, psychiatric, and cognitive manifestations. The NMDAR is a key signaling node for neurovascular coupling, the mechanism by which cerebral blood perfusion is enhanced to meet local metabolic requirements from increased neuronal activity. Therefore, anti-NMDAR encephalitis may disrupt neurovascular coupling and induce cognitive deficits. This study examined neurovascular coupling and cognitive function in anti-NMDAR encephalitis patients to identify prognostic biomarkers, reveal potential pathogenic mechanisms, and provide clues to possible therapeutic strategies. In this study, twenty-three anti-NMDAR encephalitis patients and thirty healthy controls received neuropsychological testing and multimodal magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was calculated from arterial spin labeling, and regional homogeneity (ReHo) was computed from functional MRI. Pearson's correlation coefficients between CBF and ReHo were calculated to obtain neurovascular coupling. At the whole gray matter level, CBF‒ReHo coupling was reduced in patients compared to healthy controls. At the regional level, CBF‒ReHo was significantly lower among patients in the precentral gyrus, frontal gyrus, insula, cuneus, inferior parietal lobe, supramarginal gyrus, angular gyrus, precuneus, temporal gyrus, and temporal pole. Reduced CBF‒ReHo in the left superior medial frontal gyrus of patients was significantly correlated with a deficit in verbal inhibition control, and the reduced CBF‒ReHo in the left insula was significantly correlated with impaired executive function. In conclusion, anti-NMDAR encephalitis is associated with both global and regional disruptions in neurovascular coupling that may in turn lead to deficits in specific cognitive domains.