The role of lncFABP4 in modulating adipogenic differentiation in buffalo intramuscular preadipocytes.

Intramuscular fat (IMF) is a crucial determinant of meat quality and is influenced by various regulatory factors. Despite the growing recognition of the important role of long noncoding RNAs (lncRNAs) in IMF deposition, the mechanisms underlying buffalo IMF deposition remain poorly understood. In this study, we identified and characterized a lncRNA, lncFABP4, which is transcribed from the antisense strand of fatty acid-binding protein 4 (FABP4). lncFABP4 inhibited cell proliferation in buffalo intramuscular preadipocytes. Moreover, lncFABP4 significantly increased intramuscular preadipocyte differentiation, as indicated by an increase in the expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARG), CCAAT enhancer binding protein alpha (C/EBPα), and FABP4. Mechanistically, lncFABP4 was found to have the potential to regulate downstream gene expression by participating in protein-protein interaction pathways. These findings contribute to further understanding of the intricate mechanisms through which lncRNAs modulate intramuscular adipogenesis in buffaloes.

From suppressor to enhancer: IL-10's alternative role in CAR-T cell therapies against solid tumors.

Aiming to improve the effector function of CAR-T cells, Zhao et al.1 report that IL-10 metabolically reprograms CAR-T cells, and this promotes their effectiveness against solid tumors and challenges IL-10's perceived role as merely immunosuppressive. This simple but promising strategy fosters durable immune memory and eagerly awaits validation in clinical trials.

Nitrogen-Doped CoP with optimized d-Band center as bidirectional electrocatalyst for high areal capacity of Li-S battery.

Lithium polysulfide (LiPSs) shuttle effect and difficulties with Li2S oxidation are hinder the marketization of lithium-sulfur batteries. We suggest using a bidirectional catalyst in the sulfur host to solve these problems. We produced a nitrogen-doped cobalt phosphide (N-CoP@NC) as a sulfur carrier in this work. The introduction of nitrogen into cobalt phosphide enhances the electron transmission speed and forms shorter Co-N bonds. As a result, new defect energy levels are introduced, leading to an increase in the charge number of Co central atoms, which abate the Li-S and SS bonds in Li2S and Li2S4, thereby promoting the oxidation of Li2S during charging, as well as the alteration process of LiPSs during charge and discharge. Additionally, the crystal flaws that result in increased Co-S bond formation help to boost polysulfides' adsorption ability. The Li-S batteries shows outstanding cyclability when paired with this electrocatalyst, demonstrating a minimal capacity degradation rate of only 0.07 % per cycle over 500 cycles at a rate of 0.5C. As a result, incorporating anion doping in the host emerges as a promising method for crafting materials tailored for Li-S batteries.

Hypoxic Bone Mesenchymal Stem Cell-Derived Exosomes Direct Schwann Cells Proliferation, Migration, and Paracrine to Accelerate Facial Nerve Regeneration via circRNA_Nkd2/miR-214-3p/MED19 Axis.

Background: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism. Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments. Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p. Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI.

Evaluation of generic EMG-Torque models across two Upper-Limb joints.

Advanced single-use dynamic EMG-torque models require burdensome subject-specific calibration contractions and have historically been assumed to produce lower error than generic models (i.e., models that are identical across subjects and muscles). To investigate this assumption, we studied generic one degree of freedom (DoF) models derived from the ensemble median of subject-specific models, evaluated across subject, DoF and joint. We used elbow (N = 64) and hand-wrist (N = 9) datasets. Subject-specific elbow models performed statistically better [5.79 ± 1.89 %MVT (maximum voluntary torque) error] than generic elbow models (6.21 ± 1.85 %MVT error). However, there were no statistical differences between subject-specific vs. generic models within each hand-wrist DoF. Next, we evaluated generic models across joints. The best hand-wrist generic model had errors of 6.29 ± 1.85 %MVT when applied to the elbow. The elbow generic model had errors of 7.04 ± 2.29 %MVT when applied to the hand-wrist. The generic elbow model was statistically better in both joints, compared to the generic hand-wrist model. Finally, we tested Butterworth filter models (a simpler generic model), finding no statistical differences between optimum Butterworth and subject-specific models. Overall, generic models simplified EMG-torque training without substantive performance degradation and provided the possibility of transfer learning between joints.

THEMIS is a substrate and allosteric activator of SHP1, playing dual roles during T cell development.

THEMIS plays an indispensable role in T cells, but its mechanism of action has remained highly controversial. Using the systematic proximity labeling methodology PEPSI, we identify THEMIS as an uncharacterized substrate for the phosphatase SHP1. Saturated mutagenesis assays and mass spectrometry analysis reveal that phosphorylation of THEMIS at the evolutionally conserved Tyr34 residue is oppositely regulated by SHP1 and the kinase LCK. Similar to THEMIS-/- mice, THEMISY34F/Y34F knock-in mice show a significant decrease in CD4 thymocytes and mature CD4 T cells, but display normal thymic development and peripheral homeostasis of CD8 T cells. Mechanistically, the Tyr34 motif in THEMIS, when phosphorylated upon T cell antigen receptor activation, appears to act as an allosteric regulator, binding and stabilizing SHP1 in its active conformation, thus ensuring appropriate negative regulation of T cell antigen receptor signaling. However, cytokine signaling in CD8 T cells fails to elicit THEMIS Tyr34 phosphorylation, indicating both Tyr34 phosphorylation-dependent and phosphorylation-independent roles of THEMIS in controlling T cell maturation and expansion.

Strong gelation capacity of a pectin-like polysaccharide in the presence of K+ ion.

In the present study, a pectin-like apple polysaccharide (AP) obtained by metal precipitation technique was demonstrated to show strong gelling capacity in the presence of K+ ion upon cooling. Increasing amount of K+ addition monotonically promoted the gelation of AP, as characterized by the increased gelation temperature (Tgel), gel melting temperature (Tmelt) and the gel strength. Compared with K+ ion, Na+ was unable to induce AP gelation even at high ionic concentrations, but other monovalent cations (Rb+, Cs+) can induce the gelation as in the case of K+ addition. At room temperature, the minimum cationic concentration as required to induce AP gelation followed the order of K+ ≈ Cr+ (8 mM) > Rb+ (3.5 mM), indicating that cationic radius (Na+ < K+ < Rb+ < Cs+) played a dominant role in inducing AP gelation, but other factors may also be involved. Finally, the gelation behavior of AP in the presence of K+ was explained as the suppressed intermolecular electrostatic repulsion between AP chains due to the strong electrostatic shielding effect of K+, which led to the formation of a gel network mediated by intermolecular hydrogen bonding. This reported gelation property may allow AP to find application as a new gelling polysaccharide.

Mo2C-MoP heterostructure regulate the adsorption energy of electrocatalysts in high-performance Li-S batteries.

The cathodic polysulfides electrocatalyst, such as Mo2C, offers a promising approach to mitigate the shuttling effect by providing strong polysulfide adsorption and catalyst abilities to improve the electrochemical performance of Lithium-sulfur (Li-S) batteries. However, according to the Sabatier principle, excessive adsorption of Mo2C undermines the conversion of polysulfides. This undesirable effect can be mitigated by forming the heterostructure of Mo2C-MoP. Even more importantly, the introduction of MoP can prevent the surface gelation of Mo2C and expose more active sites. Consequently, the Li-S batteries with the Mo2C-MoP sulfur host exhibit outstanding long-term cycling stability, showcasing a mere 0.035% capacity decay per cycle over 800 cycles at 1 C. This work on the balance between adsorption capacity and catalytic active of cathodic polysulfides electrocatalyst provides a new vision for realizing a high-performance Li-S batteries.

Murine trophoblast organoids as a model for trophoblast development and CRISPR-Cas9 screening.

The placenta becomes one of the most diversified organs during placental mammal radiation. The main in vitro model for studying mouse trophoblast development is the 2D differentiation model of trophoblast stem cells, which is highly skewed to certain lineages and thus hampers systematic screens. Here, we established culture conditions for the establishment, maintenance, and differentiation of murine trophoblast organoids. Murine trophoblast organoids under the maintenance condition contain stem cell-like populations, whereas differentiated organoids possess various trophoblasts resembling placental ones in vivo. Ablation of Nubpl or Gcm1 in trophoblast organoids recapitulated their deficiency phenotypes in vivo, suggesting that those organoids are valid in vitro models for trophoblast development. Importantly, we performed an efficient CRISPR-Cas9 screening in mouse trophoblast organoids using a focused sgRNA (single guide RNA) library targeting G protein-coupled receptors. Together, our results establish an organoid model to investigate mouse trophoblast development and a practicable approach to performing forward screening in trophoblast lineages.

Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness.

Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.

Preparation and Dispersion Performance of Hydrophobic Fumed Silica Aqueous Dispersion.

Hydrophobic fumed silica (HFS) is a commonly used rheology additive in waterborne coatings. A series of experiments were conducted on the HFS-dispersing technology in this study. The size and structure of HFS primary particles were observed via transmission electron microscopy (TEM). The measurement results of the TEM were D50 = 13.6 nm and D90 = 19.7 nm, respectively. The particle size and dispersion performance of HFS were tested via dynamic light scattering (DLS). Additionally, the HFS aqueous dispersion was prepared and compounded with waterborne polyacrylic latex and polyurethane resin. The elemental distribution of the coatings was characterized using energy dispersive spectroscopy (EDS). The results show that the HFS in a non-ionic polymer dispersant had the best dispersion performance. The particle size of the HFS in the aqueous dispersion is related to the dispersion conditions. Under optimized conditions, the HFS aqueous dispersion can be prepared with a particle size of D50 = 27.2 nm. The HFS aqueous dispersion has stable storage stability. Even after storage for 47 d, the particle size still did not change significantly.

miR-21-5p Inhibits the Proliferation, Migration, and Invasion of Glioma by Targeting S100A10.

S100A10, a member of the S100 protein family, is upregulated in multiple human malignancies and plays a key role in regulating tumor progression. This study aimed to reveal the underlying mechanism by which S100A10 in regulates the proliferation, migration, and invasion of glioma. The expression and clinical information data of S100A10 were downloaded from public databases (TCGA, CGGA, and GEPIA2). S100A10 expression levels in glioma tumor tissues and adjacent nontumor tissues were compared by immunohistochemistry (IHC). The functional roles of S100A10 in glioma were assessed by cell counting kit-8 (CCK-8) cell proliferation assay, wound healing assay, transwell assay, and flow cytometry. miRDB and double luciferase assay were used to predict and identify potential S100A10 mRNA-complementary miRNAs, and the roles of miR-21-5p in glioma cell were examined by targeted knockdown or overexpression miR-21-5p in glioma cell lines. We found that S100A10 was overexpressed in glioma tissues and predicted a worse prognosis. S100A10 knockdown significantly inhibited glioma cell proliferation, invasion, and migration. Furthermore, we demonstrated that miR-21-5p inhibits glioma proliferation, migration, and invasion by targeting S100A10. This study showed S100A10 was a new prognostic predictor among glioma patients and provided new insights into the pathogenesis of gliomas, suggesting that miR-21-5p /S100A10 axis may serve as a valuable therapeutic target for glioma.

Charging CAR by electrostatic power.

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for cancer treatment. CAR is a synthetic immune receptor that recognizes tumor antigen and activates T cells through multiple signaling pathways. However, the current CAR design is not as robust as T cell receptor (TCR), a natural antigen receptor with high sensitivity and efficiency. TCR signaling relies on specific molecular interactions, and thus electrostatic force, the major force of molecular interactions, play critical roles. Understanding how electrostatic charge regulates TCR/CAR signaling events will facilitate the development of next-generation T cell therapies. This review summarizes recent findings on the roles of electrostatic interactions in both natural and synthetic immune receptor signaling, specifically that in CAR clustering and effector molecule recruitments, and highlights potential strategies for engineering CAR-T cell therapy by leveraging charge-based interactions.

Analysis of Lipid Molecule Profiling and Conversion Pathway in Mandarin Fish (Siniperca chuatsi) during Fermentation via Untargeted Lipidomics.

Lipids are the key aroma contributors and nutrients in fermented fish products. A total of 376 lipid molecules were identified in mandarin fish during fermentation by untargeted lipidomics, including glycerolipids, glycerophospholipids, lysoglycerophospholipid, sphingolipids, fatty acids (FAs), and sterol lipids. Both lipid composition and content changed dynamically during fermentation. Triglyceride (TAG, 30.05%) and phosphatidylcholine (PC, 14.87%) were the two major lipids, with especially 39.36% saturated FAs in PCs and 35.34% polyunsaturated FAs in TAGs. The content of TAGs and PCs reached a peak point at 0 and 6 days, respectively. Fermented mandarin fish expressed a high nutritional value, and the ratio of total linoleic acid/total linolenic acid was about 5:1. Glycerophospholipid metabolism was a potential metabolic pathway, and the oxidation of derived FAs contributed to flavor. These data progress in understanding lipid dynamic variation during fermentation and provide thoughts on controlling the flavor quality and safety of fermented fish products.

Branched-chain aminotransferase 1 promotes Schwann cell migration and proliferation to accelerate facial nerve regeneration through the Twist/FoxC1 and Sox2 pathways.

Facial paralysis caused by injury to the facial nerve is common clinical presentation resulting in significant physical and psychological damage. In addition, due to the lack of understanding about the mechanisms of injury and repair and the lack of effective treatment targets, the clinical treatment outcomes for such patients remain poor. Schwann cells (SCs) have a central role in the regeneration of nerve myelin. In a rat model of facial nerves crush injury, we found that branched-chain aminotransferase 1 (BCAT1) was upregulated after injury. Moreover, it had a positive role in nerve repair. Using intervention methods such as gene knockdown, overexpression, and protein-specific inhibitors, combined with detection methods such as CCK8, Transwell, EdU, and flow cytometry, we demonstrated that BCAT1 significantly enhanced the migration and proliferation of SCs. It affected SC cell migration by regulating the Twist/Foxc1 signal axis and promoted cell proliferation by directly regulating the expression of SOX2. Similarly, animal experiments demonstrated that BCAT1 promotes facial nerve repair, improving nerve function and myelin regeneration by activating both the Twist/Foxc1 and SOX2 axes. In sum, BCAT1 promotes SC migration and proliferation, suggesting its potential as a key molecular target for improving the outcome of facial nerve injury repairs.

Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.

The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRß depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.

Design of diversified chimeric antigen receptors through rational module recombination.

Chimeric antigen receptor (CAR)-T cells have shown great promise in cancer therapy. However, the anti-tumor efficiency is limited due to the CAR-induced T cell apoptosis or exhaustion. The intracellular domain of CAR comprised of various signaling modules orchestrates CAR-T cell behaviors. The modularity of CAR signaling domain functions as the "mainboard" to assemble diversified downstream signaling components. Here, we implemented the modular recombination strategy to construct a library of CARs with synthetic co-signaling modules adopted from immunoglobin-like superfamily (IgSF) and tumor necrosis factor receptor superfamily (TNFRSF). We quantitatively characterized the signaling behaviors of these recombinants by both NFAT and NF-κB reporter, and identified a set of new CARs with diverse signaling behaviors. Specifically, the 28(NM)-BB(MC) CAR-T cells exhibited improved cytotoxicity and T cell persistence. The synthetic approach can promote our understanding of the signaling principles of CAR molecule, and provide a powerful tool box for CAR-T cell engineering.