Triglyceride-glucose index predicts sepsis-associated acute kidney injury and length of stay in sepsis: A MIMIC-IV cohort study.

Background: Inflammation and stress response may be related to the occurrence of sepsis-associated acute kidney injury (SA-AKI) in patients with sepsis.Insulin resistance (IR) is closely related to the stress response, inflammatory response, immune response and severity of critical diseases. We assume that the triglyceride-glucose (TyG) index, an alternative indicator for IR, is associated with the occurrence of SA-AKI in patients with sepsis. Methods: Data were obtained from The Medical Information Mart for Intensive Care-IV(MIMIC-IV) database in this retrospective cohort study. Univariate and multivariate logistic regression analysis and multivariate restricted cubic spline(RCS) regression were conducted to evaluate the association between TyG index and SA-AKI, length of stay (LOS). Subgroup and sensitivity analyses were performed to verify the robustness of the results. Results: The study ultimately included data from 1426 patients with sepsis, predominantly of white ethnicity (59.2%) and male sex (56.4%), with an SA-AKI incidence rate of 78.5%. A significant linear association was observed between the TyG index and SA-AKI (OR, 1.40; 95% confidence interval(CI) [1.14-1.73]). Additionally, the TyG index demonstrated a significant correlation with the length of stay (LOS) in both the hospital (ß, 1.79; 95% CI [0.80-2.77]) and the intensive care unit (ICU) (ß, 1.30; 95% CI [0.80-1.79]). Subgroup and sensitivity analyses confirmed the robustness of these associations. Conclusion: This study revealed a strong association between the TyG index and both SA-AKI and length of stay in patients with sepsis. These findings suggest that the TyG index is a potential predictor of SA-AKI and the length of hospitalization in sepsis cases, broadening its application in this context. However, further research is required to confirm whether interventions targeting the TyG index can genuinely enhance the clinical outcomes of patients with sepsis.

CD8 T cell-derived perforin regulates macrophage-mediated inflammation in a murine model of gout.

OBJECTIVES: Gout is characterized by hyperuricemia and recurrent inflammatory episodes caused by intra-articular crystal deposition of monosodium urate (MSU). There is a clear relationship between gout and metabolic syndrome. Recent evidence indicates that perforin plays a role in regulating glucose homeostasis and provides protection in diet-induced non-alcoholic steatohepatitis models. However, the impact of perforin on immune inflammation in gout remains unclear. METHODS: We induced acute gout models in both wild-type (WT) mice and Prf1null mice by administering intra-articular injections of MSU crystals. We compared the ankle joint swelling and the histological score between the two groups. Furthermore, we investigated underlying mechanisms through in vitro co-culture experiments involving CD8 T cells and macrophages. RESULTS: In this study, Prf1null mice showed significantly more pronounced ankle swelling with increased inflammatory cell infiltrations compared with WT mice 24 h after local MSU injection. Moreover, MSU-induced Prf1null mice exhibited increased accumulation of CD8 T cells but not NK cells. Perforin-deficient CD8 T cells displayed reduced cytotoxicity towards bone marrow-derived M0 and M1 macrophages and promoted TNF-α secretion from macrophage. CONCLUSIONS: Perforin from CD8 T cells limits joint inflammation in mice with acute gout by downregulating macrophage-mediated inflammation. Key Points • Perforin deficiency increased swelling in the ankle joints of mice upon MSU injection. • Perforin deficiency is associated with increased immune cell recruitment and severe joint damage in gout. • Perforin regulated CD8 T cell accumulation in gout and promoted CD8 T cell cytotoxicity towards M0 and M1 macrophages. • CD8 T cell-derived perforin regulated pro-inflammatory cytokine secretion of macrophage.

Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

Chasing weakly-bound biological water in aqueous environment near the peptide backbone by ultrafast 2D infrared spectroscopy.

There has been a long-standing debate as to how many hydrogen bonds a peptide backbone amide can form in aqueous solution. Hydrogen-bonding structural dynamics of N-ethylpropionamide (a ß-peptide model) in water was examined using infrared (IR) spectroscopy. Two amide-I sub bands arise mainly from amide C=O group that forms strong H-bonds with solvent water molecules (SHB state), and minorly from that involving one weak H-bond with water (WHB state). This picture is supported by molecular dynamics simulations and ab-initio calculations. Further, thermodynamics and kinetics of the SHB and WHB species were examined mainly by chemical-exchange two-dimensional IR spectroscopy, yielding an activation energy for the SHB-to-WHB exchange of 13.25 ± 0.52 kJ mol‒1, which occurs in half picosecond at room temperature. Our results provided experimental evidence of an unstable water molecule near peptide backbone, allowing us to gain more insights into the dynamics of the protein backbone hydration.

Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient.

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-ß42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-ß42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-ß at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aß-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aß-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.

Sortilin-Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain.

Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high-energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two-pore-domain K+ channel (K2P) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin-mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP.

Functional properties and skin care effects of sodium trehalose sulfate.

BACKGROUND: It is known that heparinoid, a mucopolysaccharide polysulfate, is effective in improving rough skin and promoting blood circulation as medicines for diseased areas. However, heparinoid has a molecular weight of more than 5000 and cannot penetrate healthy stratum corneum. OBJECTIVE: We tested the efficacy of sulfated oligosaccharides with a molecular weight of less than 2000 on the human skin barrier function and moisturizing function. METHODS: We measured the transepidermal water loss (TEWL) of a three-dimensional human epidermis model cultured for 3 days after topical application of sulfated oligosaccharides, then observed the effects on TEWL suppression. The mRNA levels of proteins involved in intercellular lipid transport and storage in the stratum corneum, and moisture retention were measured using RT-qPCR. RESULTS: An increase in the mRNA levels of the ATP-binding cassette subfamily A member 12 (ABCA12), which transports lipids into stratum granulosum, was confirmed. Increases were also observed in the mRNA levels of filaggrin (FLG), which is involved in the generation of natural moisturizing factors, and of caspase-14, calpain-1 and bleomycin hydrolase, which are involved in the degradation of FLG. Antibody staining confirmed that the application of sodium trehalose sulfate to 3D model skin resulted in more ABCA12, ceramide, transglutaminase1, and FLG than those in controls. In a randomized, placebo-controlled, double-blind study, participants with low stratum corneum water content applied a lotion and emulsion containing sodium trehalose sulfate to their faces for 4 weeks. Sodium trehalose sulfate decreased the TEWL and increased the stratum corneum water content. CONCLUSION: These results suggest that cosmetics containing sodium trehalose sulfate act on the epidermis by increasing barrier factors and moisturizing factors, thereby ameliorating dry skin.

Growth, biofilm formation, and motility of Listeria monocytogenes strains isolated from food and clinical samples located in Shanghai (China).

Listeria monocytogenes is a common foodborne pathogen that frequently causes global outbreaks. In this study, the growth characteristics, biofilm formation ability, motility ability and whole genome of 26 L. monocytogenes strains isolated from food and clinical samples in Shanghai (China) from 2020 to 2022 were analyzed. There are significant differences among isolates in terms of growth, biofilm formation, motility, and gene expression. Compared with other sequence type (ST) types, ST1930 type exhibited a significantly higher maximum growth rate, the ST8 type demonstrated a stronger biofilm formation ability, and the ST121 type displayed greater motility ability. Furthermore, ST121 exhibited significantly high mRNA expression levels compared with other ST types in virulence genes mpl, fbpA and fbpB, the quorum sensing gene luxS, starvation response regulation gene relA, and biofilm adhesion related gene bapL. Whole-genome sequencing (WGS) analyses indicated the isolates of lineage I were mostly derived from clinical, and the isolates of lineage II were mostly derived from food. The motility ability, along with the expression of genes associated with motility (motA and motB), exhibited a significantly higher level in lineage II compared with lineage I. The isolates from food exhibited significantly higher motility ability compared with isolates from clinical. By integrating growth, biofilm formation, motility phenotype with molecular and genotyping information, it is possible to enhance comprehension of the association between genes associated with these characteristics in L. monocytogenes.

Attenuation of inflammatory bowel disease by oral administration of mucoadhesive polydopamine-coated yeast ß-glucan via ROS scavenging and gut microbiota regulation.

Treatment for inflammatory bowel disease (IBD) is challenging since current anti-inflammatory and immunosuppressive therapies do not address the underlying causes of the illness, which include increased levels of reactive oxygen species (ROS) and dysbiosis of the gut commensal microbiota. Additionally, these treatments often have systemic off-target effects and adverse side effects. In this study, we have developed a prebiotic yeast ß-glucan nanocomplex coated with bio-adhesive polydopamine (YBNs@PDA) to effectively prolong their retention time in the gastrointestinal (GI) tract. The oral administration of YBNs@PDA restored the epithelium barriers, reduced ROS levels, and minimized systemic drug exposure while improved therapeutic efficacy in an acute colitis mouse model. Furthermore, 16S ribosomal RNA genes sequencing demonstrated a higher richness and diversity in gut microflora composition following the treatments. In particular, YBNs@PDA markedly augmented the abundance of Lachnospiraceae NK4A136 and Bifidobacterium, both of which are probiotics with crucial roles in relieving colitis via retaining gut homeostasis. Cumulatively, these results demonstrate that the potential of YBNs@PDA as a novel drug-free, ROS-scavenging and gut microbiota regulation nanoplatform for the treatment of GI disorders.

Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) is strongly associated with neuroinflammation, and type I interferons (IFN-I) play a crucial role in regulating immune and inflammatory responses. However, the specific features of IFN in different cell types and the underlying mechanisms of PD have yet to be fully described. In this study, we analyzed the GSE157783 dataset, which includes 39,024 single-cell RNA sequencing results for five PD patients and six healthy controls from the Gene Expression Omnibus database. After cell type annotation, we intersected differentially expressed genes in each cell subcluster with genes collected in The Interferome database to generate an IFN-I-stimulated gene set (ISGs). Based on this gene set, we used the R package AUCell to score each cell, representing the IFN-I activity. Additionally, we performed monocle trajectory analysis, and single-cell regulatory network inference and clustering (SCENIC) to uncover the underlying mechanisms. In silico gene perturbation and subsequent experiments confirm NFATc2 regulation of type I interferon response and neuroinflammation. Our analysis revealed that microglia, endothelial cells, and pericytes exhibited the highest activity of IFN-I. Furthermore, single-cell trajectory detection demonstrated that microglia in the midbrain of PD patients were in a pro-inflammatory activation state, which was validated in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model as well. We identified transcription factors NFATc2, which was significantly up-regulated and involved in the expression of ISGs and activation of microglia in PD. In the 1-Methyl-4-phenylpyridinium (MPP+)-induced BV2 cell model, the suppression of NFATc2 resulted in a reduction in IFN-ß levels, impeding the phosphorylation of STAT1, and attenuating the activation of the NF-κB pathway. Furthermore, the downregulation of NFATc2 mitigated the detrimental effects on SH-SY5Y cells co-cultured in conditioned medium. Our study highlights the critical role of microglia in type I interferon responses in PD. Additionally, we identified transcription factors NFATc2 as key regulators of aberrant type I interferon responses and microglial pro-inflammatory activation in PD. These findings provide new insights into the pathogenesis of PD and may have implications for the development of novel therapeutic strategies.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma.

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

Self-esteem mediates the relationship between the parahippocampal gyrus and decisional procrastination at resting state.

When faced with a conflict or dilemma, we tend to postpone or even avoid making a decision. This phenomenon is known as decisional procrastination. Here, we investigated the neural correlates of this phenomenon, in particular the parahippocampal gyrus (PHG) that has previously been identified in procrastination studies. In this study, we applied an individual difference approach to evaluate participants' spontaneous neural activity in the PHG and their decisional procrastination levels, assessed outside the fMRI scanner. We discovered that the fractional amplitude of low-frequency fluctuations (fALFF) in the caudal PHG (cPHG) could predict participants' level of decisional procrastination, as measured by the avoidant decision-making style. Importantly, participants' self-esteem mediated the relationship between the cPHG and decisional procrastination, suggesting that individuals with higher levels of spontaneous activity in the cPHG are likely to have higher levels of self-esteem and thus be more likely to make decisions on time. In short, our study broadens the PHG's known role in procrastination by demonstrating its link with decisional procrastination and the mediating influence of self-esteem, underscoring the need for further exploration of this mediation mechanism.

Structural insights into ion selectivity and transport mechanisms of Oryza sativa HKT2;1 and HKT2;2/1 transporters.

Plant high-affinity K+ transporters (HKTs) play a pivotal role in maintaining the balance of Na+ and K+ ions in plants, thereby influencing plant growth under K+-depleted conditions and enhancing tolerance to salinity stress. Here we report the cryo-electron microscopy structures of Oryza sativa HKT2;1 and HKT2;2/1 at overall resolutions of 2.5 Å and 2.3 Å, respectively. Both transporters adopt a dimeric assembly, with each protomer enclosing an ion permeation pathway. Comparison between the selectivity filters of the two transporters reveals the critical roles of Ser88/Gly88 and Val243/Gly243 in determining ion selectivity. A constriction site along the ion permeation pathway is identified, consisting of Glu114, Asn273, Pro392, Pro393, Arg525, Lys517 and the carboxy-terminal Trp530 from the neighbouring protomer. The linker between domains II and III adopts a stable loop structure oriented towards the constriction site, potentially participating in the gating process. Electrophysiological recordings, yeast complementation assays and molecular dynamics simulations corroborate the functional importance of these structural features. Our findings provide crucial insights into the ion selectivity and transport mechanisms of plant HKTs, offering valuable structural templates for developing new salinity-tolerant cultivars and strategies to increase crop yields.

Joint equalization of RSOP and PMD fused probability-aware with square-root cubature Kalman filter for the PDM PCS-64QAM system under extreme scenarios.

Extreme scenario of lightning strikes would generate ultra-fast rotation of state-of-polarization (RSOP) up to 5.1 Mrad/s and large polarization mode dispersion (PMD) in optical ground wire (OPGW). Unfortunately, the conventional multiple modulus algorithm (MMA) cannot equalize these polarization impairments in polarization division multiplexing (PDM) probabilistic constellation shaping (PCS)-64QAM system. Moreover, due to unavoidable linearization errors and higher modulation order, the extended Kalman filter based on measurement equations of concatenated multiplication (EKF-CM) is highly unstable and fails under such scenarios. To address the above issues, we have proposed a joint equalization scheme of PMD and RSOP, which fuses probability-aware with square-root cubature Kalman filter (PA-SCKF). Firstly, according to the characteristic that the amplitude of PCS signals obeys mixed Rician distribution, the scheme combines maximum a posteriori criterion to obtain the optimal radius of constellation ring which the received symbol belongs to, for the sake of calculating the innovations of SCKF. Secondly, it performs joint equalization of PMD and RSOP impairments based on SCKF and time-frequency conversion architecture. 28GBaud PDM PCS-64QAM simulation results demonstrate that our scheme can jointly equalize maximum impairments of 8.34 Mrad/s RSOP and 90ps DGD under entropy of 4.5bits/symbol. Additionally, only 0.9 dB OSNR penalty is obtained after joint equalization of 6 Mrad/s RSOP with 70ps DGD impairments. Even under entropy of 5.5bit/symbol, it can still jointly equalize impairments of 6.05 Mrad/s RSOP with 60ps DGD. Furthermore, 16GBaud PCS-64QAM experimental results indicate that the maximum joint equalization performances of PA-SCKF scheme under entropy of 4.5bit/symbol and 5bit/symbol are 17 Mrad/s RSOP with 52ps DGD, and 9 Mrad/s RSOP with 52ps DGD, respectively. These results manifest that our PA-SCKF scheme outperforms both MMA and EKF-CM schemes. Importantly, its complexity is on an order of O(Llog2 L), which is comparable to that of EKF-CM scheme.

High-Risk Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy versus Transarterial Chemoembolization.

Objective: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients. Methods: Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups. Results: After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47-0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39-0.8; P, 0.01) for PFS outperforming TACE. Conclusion: HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.

LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice.

BACKGROUND: LDL receptor-related protein-1 (LRP1) is a cell-surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte-specific LRP1 deficiency (hLRP1KO) promotes diet-induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic glycogenesis. METHODS: Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector (AAV8) were used to overexpress the truncated ß-chain (ß∆) of LRP1 both in vitro and in vivo. RESULTS: On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose- and time-dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3ß, increased levels of phosphorylated glycogen synthase (GYS), and diminished glycogen synthesis in insulin-stimulated HepG2 cells, which was restored by exogenous expression of the ß∆-chain. By contrast, AAV8-mediated hepatic ß∆-chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet (HFD)-fed mice. CONCLUSION: Our data revealed that LRP1, especially its ß-chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.

LettuceDB: an integrated multi-omics database for cultivated lettuce.

Crop genomics has advanced rapidly during the past decade, which generated a great abundance of omics data from multi-omics studies. How to utilize the accumulating data becomes a critical and urgent demand in crop science. As an attempt to integrate multi-omics data, we developed a database, LettuceDB (https://db.cngb.org/lettuce/), aiming to assemble multidimensional data for cultivated and wild lettuce germplasm. The database includes genome, variome, phenome, microbiome and spatial transcriptome. By integrating user-friendly bioinformatics tools, LettuceDB will serve as a one-stop platform for lettuce research and breeding in the future. Database URL: https://db.cngb.org/lettuce/.

A magnetic calcium phosphate for selective capture of multi-phosphopeptides.

The specific enrichment of multi-phosphopeptides in the presence of non-phosphopeptides and mono-phosphopeptides was still a challenge for phosphoproteomics research. Most of these enrichment materials relied on Zn, Ti, Sn, and other rare precious metals as the bonding center to enrich multi-phosphopeptides while ignoring the use of common metal elements. The addition of rare metals increased the cost of the experiment, which was not conducive to their large-scale application in biomedical proteomics laboratories. In addition, multiple high-speed centrifugation steps also resulted in the loss of low-abundance multi-phosphopeptides in the treatment procedure of biological samples. This study proposed the use of calcium, a common element, as the central bonding agent for synthesizing magnetic calcium phosphate materials (designated as CaP-Fe3O4). These materials aim to capture multi-phosphopeptides and identifying phosphorylation sites. The current results demonstrate that CaP-Fe3O4 exhibited excellent selection specificity, high sensitivity, and stability in the enrichment of multi-phosphopeptides and the identification of phosphorylation sites. Additionally, the introduction of magnetic separation not only reduced the time required for multi-phosphopeptides enrichment but also prevented the loss of these peptides during high-speed centrifugation. These findings contribute to the widespread application and advancement of phosphoproteomics research.

Changes in health-promoting metabolites associated with high-altitude adaptation in honey.

The levels of metabolites in honey are influenced by floral origin, production region, and bee species. However, how environmental factors affect honey quality remains unclear. Based on untargeted metabolomics and using UPLC Q-Orbitrap MS, we analyzed 3596 metabolites in 51 honey samples from Yunnan and Shennongjia. Comparative analysis revealed that geniposidic acid, kynurenic acid and caffieine accumulated at significantly different levels between Shennongjia and Yunnan honey. Based on cluster structure analysis, 36 Yunnan honey samples were divided into two distinct groups by altitude. Notably, quercetin, hyperoside, taxifolin, rutin, tryptophan, astragalin and phenylalanine were higher levels in high-altitude honey (>1700 m), whereas abscisic acid was higher levels in low-altitude honey (≤1700 m). Among these, significantly elevated levels of hyperoside, taxfolin, astragalin, and tryptophan were observed in honey collected from high-altitude areas in Shennongjia. Our findings highlight the effect of altitude on honey health-promoting components, providing valuable insights into honey quality.