Pyramidal neurons proportionately alter the identity and survival of specific cortical interneuron subtypes.

The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in driving the terminal differentiation and maintaining the survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types to which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin interneurons alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscore the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.

DeepCBA: A deep learning framework for gene expression prediction in maize based on DNA sequences and chromatin interactions.

Chromatin interactions create spatial proximity between distal regulatory elements and target genes in the genome, which has an important impact on gene expression, transcriptional regulation, and phenotypic traits. To date, several methods have been developed for predicting gene expression. However, existing methods do not take into consideration the effect of chromatin interactions on target gene expression, thus potentially reducing the accuracy of gene expression prediction and mining of important regulatory elements. In this study, we developed a highly accurate deep learning-based gene expression prediction model (DeepCBA) based on maize chromatin interaction data. Compared with existing models, DeepCBA exhibits higher accuracy in expression classification and expression value prediction. The average Pearson correlation coefficients (PCCs) for predicting gene expression using gene promoter proximal interactions, proximal-distal interactions, and both proximal and distal interactions were 0.818, 0.625, and 0.929, respectively, representing an increase of 0.357, 0.16, and 0.469 over the PCCs obtained with traditional methods that use only gene proximal sequences. Some important motifs were identified through DeepCBA; they were enriched in open chromatin regions and expression quantitative trait loci and showed clear tissue specificity. Importantly, experimental results for the maize flowering-related gene ZmRap2.7 and the tillering-related gene ZmTb1 demonstrated the feasibility of DeepCBA for exploration of regulatory elements that affect gene expression. Moreover, promoter editing and verification of two reported genes (ZmCLE7 and ZmVTE4) demonstrated the utility of DeepCBA for the precise design of gene expression and even for future intelligent breeding. DeepCBA is available at http://www.deepcba.com/ or http://124.220.197.196/.

Spectral CT assists differentiation of osteoblastic bone metastasis from bone island in newly diagnosed cancer patients.

OBJECTIVES: To investigate measurements derived from plain and enhanced spectral CT in differentiating osteoblastic bone metastasis (OBM) from bone island (BI). MATERIALS AND METHODS: From January to November 2020, 73 newly diagnosed cancer patients with 201 bone lesions (OBM = 92, BI = 109) having received spectral CT were retrospectively enrolled. Measurements including CT values of 40-140 keV, slope of the spectral curve, effective atomic number (Zeff), water (calcium) density, calcium (water) density, and Iodine (calcium) density were derived from manually segmented lesions on plain and enhanced spectral CT, and then analyzed using Student t-test and Pearson's correlation. Multivariate analysis was performed to build models (plain spectral model, enhanced spectral CT model, and combined model) for the discrimination of OBM and BI with performance evaluated using receiver operator characteristics curve and DeLong test. RESULTS: All features were significantly different between the BI group and OBM group (all p < 0.05), highly correlated with the corresponding features between plain and enhanced spectral CT both in OBM (r: 0.392-0.763) and BI (r: 0.430-0.544). As for the model performance, the combined model achieved the best performance (AUC = 0.925, 95% CI: 0.879 to 0.957), which significantly outperformed the plain spectral CT model (AUC = 0.815, 95% CI: 0.754 to 0.866, p < 0.001) and enhanced spectral CT model (AUC = 0.901, 95% CI: 0.852 to 0.939, p = 0.024) in differentiating OBM and BI. CONCLUSION: In addition to plain spectral CT measurements, enhanced spectral CT measurements would further significantly benefit the differential diagnosis. CLINICAL RELEVANCE STATEMENT: Measurements derived either from plain or enhanced spectral CT could provide additional valuable information to improve the differential diagnosis between OBM and BI in newly diagnosed cancer patients. KEY POINTS: • We intend to investigate plain and enhanced spectral CT measurements in differentiating OBM from BI. • Both plain and enhanced spectral CT help in discriminating OBM and BI in newly diagnosed cancer patients. • Enhanced spectral CT measurements further improve plain spectral CT measurements-based differential diagnosis.

Biomimetic Theranostic Agents with Superior NIR-II Photoacoustic and Magnetic Resonance Imaging Performance for Targeted Photothermal Therapy of Prostate Cancer.

The accurate diagnosis and treatment of prostate cancer at an early stage is crucial to reduce mortality rates. However, the limited availability of theranostic agents with active tumor-targeting abilities hinders imaging sensitivity and therapeutic efficiency. To address this challenge, we have developed biomimetic cell membrane-modified Fe2O3 nanoclusters implanted in polypyrrole (CM-LFPP), achieving photoacoustic/magnetic resonance dual-modal imaging-guided photothermal therapy of prostate cancer. The CM-LFPP exhibits strong absorption in the second near-infrared window (NIR-II, 1000-1700 nm), showing high photothermal conversion efficiency of up to 78.7% under 1064 nm laser irradiation, excellent photoacoustic imaging capabilities, and good magnetic resonance imaging ability with a T2 relaxivity of up to 48.7 s-1 mM-1. Furthermore, the lipid encapsulation and biomimetic cell membrane modification enable CM-LFPP to actively target tumors, leading to a high signal-to-background ratio of ~30.2 for NIR-II photoacoustic imaging. Moreover, the biocompatible CM-LFPP enables low-dose (0.6 W cm-2) photothermal therapy of tumors under 1064 nm laser irradiation. This technology offers a promising theranostic agent with remarkable photothermal conversion efficiency in the NIR-II window, providing highly sensitive photoacoustic/magnetic resonance imaging-guided prostate cancer therapy.

LBP1C-2 from Lycium barbarum alleviated age-related bone loss by targeting BMPRIA/BMPRII/Noggin.

Age-related bone loss is unavoidable and effective safe drugs are in great need. The fruit of Lycium barbarum was recorded to strengthen bones in the "Ben Cao Gang Mu (Compendium of Materia Medica)". However, there lacks scientific explanation. Herein, we investigated L. barbarum water extract (LBE), L. barbarum polysaccharides (LBP) and the homogeneous polysaccharide LBP1C-2 on the bone loss in adult mouse, aging mouse and ovariectomized mouse models. LBE, LBP and LBP1C-2 all markedly increased bone mass and bone strength in these models and promoted osteoblast proliferation, differentiation and ossification. Mechanistic studies showed that LBP1C-2 binds directly to the BMP receptors (BMPRIA and BMPRII) and noggin, activates the phosphorylation of Smad and disrupts the interaction between noggin and BMPs. Our results clearly elucidate the mechanism, the critical component and the direct targets of L. barbarum and provide potentially safe natural products and new drug candidate against age-related bone loss.

Precise A∙T to G∙C base editing in the allotetraploid rapeseed (Brassica napus L.) genome.

Rapeseed is an important source of oilseed crop in the world. Achieving genetic improvement has always been the major goal in rapeseed production. Single nucleotide substitution is the basis of most genetic variation underpinning important agronomic traits. Nowadays, Cas-base editing acts as an efficient tool to mediate single-base substitution at the target site. In this study, four adenine base editors (ABE) were modified to achieve adenosine base editing at different genome sites in allotetraploid Brassica napus. We designed 18 small guide RNAs to target phytoene desaturase (PDS), acetolactate synthase (ALS), CLAVATA3 (CLV3), CLV2, TRANSPARENT TESTA12 (TT12), carotenoid isomerase (CRTISO), designated de-etiolated-2 (DET2), BRANCHED1 (BRC1), zeaxanthin epoxidase (ZEP) genes, respectively. Among the four ABE systems, pBGE17 had the highest base-editing efficiency, with an average editing efficiency of 3.51%. Target sequencing results revealed that the editing window ranged from A5 to A8 of the protospacer-adjacent motif (PAM) sequence. Moreover, the ABEmax-nCas9NG system with NG PAM was developed, with a base-editing efficiency of 1.22%. These results revealed that ABE system developed in this study could efficiently induce A to G substitution and the ABE-nCas9NG system could broaden editing window in oilseed rape.

Precision Redox: The Key for Antioxidant Pharmacology.

Significance: The redox balance of cells provides a stable microenvironment for biological macromolecules to perform their physiological functions. As redox imbalance is closely related to the occurrence and development of a variety of diseases, antioxidant therapies are an attractive option. However, redox-based therapeutic strategies have not yet shown satisfactory results. To find the key reason is of great significance. Recent Advances: We emphasize the precise nature of redox regulation and elucidate the importance and necessity of precision redox strategies from three aspects: differences in redox status, differences in redox function, and differences in the effects of redox therapy. We then propose the "5R" principle of precision redox in antioxidant pharmacology: "Right species, Right place, Right time, Right level, and Right target." Critical Issues: Redox status must be considered in the context of species, time, place, level, and target. The function of a biomacromolecule and its cellular signaling role are closely dependent on redox status. Accurate evaluation of redox status and specific interventions are critical for the success of redox treatments. Precision redox is the key for antioxidant pharmacology. The precise application of antioxidants as nutritional supplements is also key to the general health of the population. Future Directions: Future studies to develop more accurate methods for detecting redox status and accurately evaluating the redox state of different physiological and pathological processes are needed. Antioxidant pharmacology should consider the "5R" principle rather than continuing to apply global nonspecific antioxidant treatments. Antioxid. Redox Signal. 34, 1069-1082.