The prelimbic cortex (PrL) is involved in the organization of operant behaviors, but the relationship between longitudinal PrL neural activity and operant learning and performance is unknown. Here, we developed deep behavior mapping (DBM) to identify behavioral microstates in video recordings. We combined DBM with longitudinal calcium imaging to quantify behavioral tuning in PrL neurons as mice learned an operant task. We found that a subset of PrL neurons were strongly tuned to highly specific behavioral microstates, both task and non-task related. Overlapping neural ensembles were tiled across consecutive microstates in the response-reinforcer sequence, forming a continuous map. As mice learned the operant task, weakly tuned neurons were recruited into new ensembles, with a bias toward behaviors similar to their initial tuning. In summary, our data suggest that the PrL contains neural ensembles that jointly encode a map of behavioral states that is fine grained, is continuous, and grows during operant learning.

Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.

Recently, KPC-producing P. aeruginosa has rapidly emerged and expanded in East China. Here we described the clinical impact and characteristics of bloodstream infections (BSIs) from the dominant KPC-producing CRPA belonging to Sequence Type (ST) 463.

Duhaldea pterocaula (Franch.) Anderb, also known as Inula pterocaula Franch (I. pterocaula), is a folk medicine of the Yi nationality in China. The Inula plants display various biological activities, including anti-nociceptive and anti-inflammatory properties. I. pterocaula has been traditionally used for the treatment of bronchitis, vasculitis, and dizziness. However, very few studies have been reported on the pharmacology of I. pterocaula. The present study aims to characterize the anti-nociceptive and anti-inflammatory properties of I. pterocaula and explore the underlying mechanism. I. pterocaula was extracted by 95% ethanol and further portioned with petroleum ether, ethyl acetate (EA) and n-butanol, sequentially, to obtain corresponding factions with different polarities. The EA fraction (IPEA) was found to be one of the most effective fractions. It demonstrated potent analgesic effects in both acute and inflammatory pain mouse models, and caused no anti-nociceptive tolerance. Furthermore, IPEA improved the tolerance of mice to morphine. IPEA also showed potent anti-inflammatory effects on LPS-induced septic mice. BIC, a GABAAR antagonist, reversed the effects of IPEA in pain and inflammation models. Collectively, GABAARs play a key role in the pharmacological effects of IPEA. I. pterocaula may be useful as a complementary or alternative therapeutic agent for the treatment of pain and inflammation.

Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030, and 10 CpGs, respectively, were established to predict health outcomes and mortality. We aimed to compare and validate the predictive ability of these scores and frailty in relation to mortality in a population-based cohort from Germany.

To evaluate the correlation and agreement between superb micro-vascular imaging (SMI) mode and the contrast-enhanced ultrasound (CEUS) mode for the ablative completeness and the volumes of ablation lesions to determine the clinical application value of SMI in follow-up after radiofrequency ablation.

Histone methylation, particularly at the H3K4 position, is thought to contribute to the specification of photoreceptor cell fate; however, the mechanisms linking histone methylation with transcription factor transactivation and photoreceptor gene expression have not yet been determined. Here, we demonstrate that MLL5 is abundantly expressed in the mouse retina. Mll5 deficiency impaired electroretinogram responses, alongside attenuated expression of a number of retina genes. Mechanistic studies revealed that MLL5 interacts with the retina-specific transcription factor, CRX, contributing to its binding to photoreceptor-specific gene promoters. Moreover, depletion of MLL5 impairs H3K4 methylation and H3K79 methylation, which subsequently compromises CRX-CBP assembly and H3 acetylation on photoreceptor promoters. Our data support a scenario in which recognition of H3K4 methylation by MLL5 is required for photoreceptor-specific gene transcription through maintaining a permissive chromatin state and proper CRX-CBP recruitment at promoter sites.

Lung adenocarcinoma (LAD) is a common malignancy; however, its underlying molecular mechanism is unclear. Circular RNAs (circRNAs) serve as significant cancer regulators. The overexpression of circRAPGEF5 in LAD tissues and cells indicated that it may be involved in promoting LAD progression. Analysis of 61 LAD tissues revealed that circRAPGEF5 was related to lymph node metastasis. Functionally, circRAPGEF5 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of LAD cells in vitro and promoted LAD cells growth in vivo. Mechanistically, dual-luciferase reporter assays confirmed direct interaction of circRAPGEF5, miR-1236-3p, and ZEB1. miR-1236-3p was upregulated and ZEB1 expression reduced after circRAPGEF5 knockdown, and the proliferation, migration, and invasion of LAD cells was inhibited. circRAPGEF5 was significantly overexpressed in LAD cell exosomes, and co-culture experiments showed that exosomal circRAPGEF5 enhanced the metastatic ability of LAD cells. Further experiments found that serum exosomal circRAPGEF5 was overexpressed in LAD; moreover, the area under the receiver operator characteristic curve of exosomal circRAPGEF5 was superior to that of serum carcinoembryonic antigen (CEA). Jointly detected serum exosomal circRAPGEF5 and serum CEA had better diagnostic performance than when detected individually. Thus, exosomal circRAPGEF5 could promote the proliferation and metastasis of LAD via the miR-1236-3p/ZEB1 axis and serum exosomal circRAPGEF5 may serve as a promising biomarker for LAD.

Browning of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of obesity and related metabolic diseases. Although small extracellular vesicles (sEVs) released from adipose tissue (sEVs-AT) have emerged as novel player that regulate systemic metabolism by connecting different organs, the role of specific contents in sEVs-AT played in WAT browning has not been clarified.

Local drug delivery has received increasing attention in recent years. However, the therapeutic efficacy of local delivery of drugs is still limited under certain scenarios, such as in the oral cavity or in wound beds after resection of tumors. In this study, we introduce a bioinspired adhesive hydrogel derived from the skin secretions of Andrias davidianus (SSAD) as a wound dressing for localized drug elution. The hydrogel was loaded with aminoguanidine or doxorubicin, and its controlled drug release and healing-promoting properties were verified in a diabetic rat palatal mucosal defect model and a C57BL/6 mouse melanoma-bearing model, respectively. The results showed that SSAD hydrogels with different pore sizes could release drugs in a controllable manner and accelerate wound healing. Transcriptome analyses of the palatal mucosa suggested that SSAD could significantly upregulate pathways linked to cell adhesion and extracellular matrix deposition and had the ability to recruit keratinocyte stem cells to defect sites. Taken together, these findings indicate that property-controllable SSAD hydrogels could be a promising biofunctional wound dressing for local drug delivery and promotion of wound healing.

Sonodynamic therapy (SDT) has rapidly advanced as a promising alternative to conventional photodynamic therapy owing to its preferable therapeutic depth. However, single-modal SDT exhibits limited efficacy due to the long-term hypoxia in tumors.

Hand-foot-mouth disease (HFMD) is a global public health issues, especially in China. It has threat the health of children under 5 years old. The early recognition of high-risk districts and understanding of epidemic characteristics can facilitate health sectors to prevent the occurrence of HFMD effectively.

Ginger (Zingiber officinale), the type species of Zingiberaceae, is one of the most widespread medicinal plants and spices. Here, we report a high-quality, chromosome-scale reference genome of ginger 'Zhugen', a traditionally cultivated ginger in Southwest China used as a fresh vegetable, assembled from PacBio long reads, Illumina short reads, and high-throughput chromosome conformation capture (Hi-C) reads. The ginger genome was phased into two haplotypes, haplotype 1 (1.53 Gb with a contig N50 of 4.68 M) and haplotype 0 (1.51 Gb with a contig N50 of 5.28 M). Homologous ginger chromosomes maintained excellent gene pair collinearity. In 17,226 pairs of allelic genes, 11.9% exhibited differential expression between alleles. Based on the results of ginger genome sequencing, transcriptome analysis, and metabolomic analysis, we proposed a backbone biosynthetic pathway of gingerol analogs, which consists of 12 enzymatic gene families, PAL, C4H, 4CL, CST, C3'H, C3OMT, CCOMT, CSE, PKS, AOR, DHN, and DHT. These analyses also identified the likely transcription factor networks that regulate the synthesis of gingerol analogs. Overall, this study serves as an excellent resource for further research on ginger biology and breeding, lays a foundation for a better understanding of ginger evolution, and presents an intact biosynthetic pathway for species-specific gingerol biosynthesis.

Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia-reperfusion (I-R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time-dependent manner during I-R injury. Further animal study revealed that, relative to control mice, CARD3-knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron-specific CARD3-overexpressing transgenic (CARD3-TG) mice exhibited increased I-R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor-β-activated kinase 1) was enhanced in CARD3-TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3-TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z-7-oxozeaenol. Conclusions These results indicate that CARD3 promotes I-R injury via activation of TAK1, which not only reveals a novel regulatory axis of I-R induced brain injury but also provides a new potential therapeutic approach for I-R injury.

We aimed to investigate the relationship between glycemic status and coronary artery disease (CAD) extent and severity in ST-elevation myocardial infarction (STEMI) patients, and further examine whether diabetes patients could benefit from glycosylated hemoglobin (HbA1c) below the recommended level.

Blocking inhibitory signaling and engaging stimulatory signaling have emerged as important therapeutic modalities for cancer immunotherapy. This study aimed to investigate immunomodulatory features of three recombinant costimulatory ligand proteins in a mouse model, which are extracellular domains of OX40-ligand (OX40L), 4-1BB-ligand (4-1BBL), or two domains in tandem, fused with the transmembrane domain of diphtheria toxin (DTT), named DTT-COS1, DTT-COS2, and DTT-COS12, respectively. In vitro study showed that DTT-COS1 and DTT-COS12 had immunological activity increasing the ratio of CD8/CD4 T cells. Treatments with DTT-COS1 and DTT-COS12 dramatically generated immune protection against the B16F10 tumor challenge in both prophylactic and therapeutic efficacy. Furthermore, regarding tumor microenvironment (TME) immunomodulation, DTT-COS1 treatment increased the proportion of CD4+ effector T cells (Teff) and decreased the expression of a suppressive cytokine. Meanwhile, DTT-COS12 reduced regulatory T cells (Treg) and improved the level of stimulatory cytokines. In addition, endogenous antibodies against OX40L/4-1BBL were generated, which may help with antitumor responses. Unexpectedly, DTT-COS2 lacked antitumor effects in vitro and in vivo. Importantly, serum analysis of liver-function associated factors and pro-inflammatory cytokines demonstrated that treatments were safe formulations in mice without signs of systemic toxicity. Remarkably, DTT-COS1 and DTT-COS12 are functional immunomodulators for mouse B16F10 melanoma, creating practical preclinical value in cancer immunotherapy.

The expression of the L-type amino acid transporter 1 (LAT1) plays a significant role in tumor progression. However, it remains unclear whether high LAT1 expression correlates with poor prognosis of solid tumor patients. Here, we conducted a meta-analysis to assess the potential of LAT1 in predicting the prognosis of tumor patients.

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.

Genistein is widely used as a pharmacological compound as well as a food additive. However, the pharmaceutical effects of Genistein on myocarditis and its potential mechanisms have not been studied in detail.

Long non-coding RNA (lncRNA) Wilms Tumor 1 Associated Protein Pseudogene 1 (WTAPP1) has been reported to be a critical player in the angiogenesis and migration of endothelial progenitor cells, while its involvement in cancer biology remains unknown. This study was carried out to investigate the role of WTAPP1 in non-small cell lung cancer (NSCLC).