Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Impact of an AI-Based laparoscopic cholecystectomy coaching program on the surgical performance: a randomized controlled trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for treating symptomatic gallstones but carries inherent risks like bile duct injury (BDI). While critical view of safety (CVS) is advocated to mitigate BDI, its real-world adoption is limited. Additionally, significant variations in surgeon performance impede procedural standardization, highlighting the need for a feasible, innovative, and effective training approach. The aim of this study is to develop an Artificial Intelligence (AI)-assisted coaching program for LC to enhance surgical education and improve surgeon's performance. MATERIALS AND METHODS: We conducted a multi-center, randomized controlled trial from May 2022 to August 2023 to assess the impact of an AI-based coaching program, SmartCoach, on novice performing LC. Surgeons and patients meeting specific inclusion criteria were randomly assigned to either a coaching group with AI-enhanced feedback or a self-learning group. The primary outcome was assessed using the Laparoscopic Cholecystectomy Rating Form (LCRF), with secondary outcomes including surgical safety, efficiency, and adverse events. Statistical analyses were performed using SPSS, with significance set at P-value less than 0.05. RESULTS: Between May 2022 and August 2023, 22 surgeons were initially enrolled from 10 hospitals, with 18 completing the study. No demographic differences were noted between coaching and self-learning groups. In terms of surgical performance (LCRF scores), the coaching group showed significant improvement over time (31 to 40, P=0.008), outperforming the self-learning group by study end (40 vs 38, P=0.032). Significant improvements in CVS achievement were also noted in the coaching group (11% to 78%, P=0.021). Overall, the coaching program was well-received, outpacing traditional educational methods in both understanding and execution of CVS and participants in the intervention group expressed strongly satisfaction with the program. CONCLUSIONS: The AI-assisted surgical coaching program effectively improved surgical performance and safety for novice surgeons in LC procedures. The model holds significant promise for advancing surgical education.

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Design Principles of Single-Atom Catalysts for Oxygen Evolution Reaction: From Targeted Structures to Active Sites.

Hydrogen production from electrolytic water electrolysis is considered a viable method for hydrogen production with significant social value due to its clean and pollution-free nature, high hydrogen production efficiency, and purity, but the anode oxygen evolution reaction (OER) process is complex and kinetically slow. Single-atom catalysts (SACs) with 100% atom utilization and homogeneous active sites often exhibit high catalytic activity and are expected to be extensively applied. The catalytic performance of OER can be further improved by precise regulation of the structure through electronic effects, coordination environment, heteroatomic doping, and so on. In this review, the mechanisms of OER under different conditions are introduced, the latest research progress of SACs in the field of OER is systematically summarized, and then the effects of various structural regulation strategies on catalytic performance are discussed, and principles and ideas for the design of SACs for OER are proposed. In the end, the outstanding issues and current challenges in this field are summarized.

Atomic-Level Regulation of Cu-Based Electrocatalyst for Enhancing Oxygen Reduction Reaction: From Single Atoms to Polymetallic Active Sites.

The slow kinetics of cathodic oxygen reduction reactions (ORR) in fuel cells and the high cost of commercial Pt-based catalysts limit their large-scale application. Cu-based single-atom catalysts (SACs) have received increasing attention as a promising ORR catalyst due to their high atom utilization, high thermodynamic activity, adjustable electronic structure, and low cost. Herein, the recent research progress of Cu-based catalysts is reviewed from single atom to polymetallic active sites for ORR. First, the design and synthesis method of Cu-based SACs are summarized. Then the atomic-level structure regulation strategy of Cu-based catalyst is proposed to improve the ORR performance. The different ORR catalytic mechanism based on the different Cu active sites is further revealed. Finally, the design principle of high-performance Cu-based SACs is proposed for ORR and the opportunities and challenges are further prospected.

Construction of n-type homogeneous to improve interfacial carrier transfer for enhanced photoelectrocatalytic hydrolysis.

Photoelectrocatalyzed hydrogen production plays an important role in the path to carbon neutrality. The construction of heterojunctions provides an ideal example of an oxygen precipitation reaction. In this work, the performance of the n-n type heterojunction CeBTC@FeBTC/NIF in the photoelectronically coupled catalytic oxygen evolution reaction (OER) reaction is presented. The efficient transfer of carriers between components enhances the catalytic activity. Besides, the construction of heterojunctions optimizes the energy level structure and increases the absorption of light, and the microstructure forms holes with a blackbody effect that also enhances light absorption. Consequently, CeBTC@FeBTC/NIF has excellent photoelectric coupling catalytic properties and requires an overpotential of only 300 mV to drive a current density of 100 mA cm-2 under illumination. More importantly, the n-n heterojunction was found to be effective in enhancing charge and photogenerated electron migration by examining the carrier density of each component and carrier diffusion at the interface.

Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers.

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers.

Coffee as a dietary strategy to prevent SARS-CoV-2 infection.

BACKGROUND: To date, most countries lifted the restriction requirement and coexisted with SARS-CoV-2. Thus, dietary behavior for preventing SARS-CoV-2 infection becomes an interesting issue on a daily basis. Coffee consumption is connected with reduced COVID-19 risk and correlated to COVID-19 severity. However, the mechanisms of coffee for the reduction of COVID-19 risk are still unclear. RESULTS: Here, we identified that coffee can inhibit multiple variants of the SARS-CoV-2 infection by restraining the binding of the SARS-CoV-2 spike protein to human angiotensin-converting enzyme 2 (ACE2), and reducing transmembrane serine protease 2 (TMPRSS2) and cathepsin L (CTSL) activity. Then, we used the method of "Here" (HRMS-exploring-recombination-examining) and found that isochlorogenic acid A, B, and C of coffee ingredients showed their potential to inhibit SARS-CoV-2 infection (inhibitory efficiency 43-54%). In addition, decaffeinated coffee still preserves inhibitory activity against SARS-CoV-2. Finally, in a human trial of 64 subjects, we identified that coffee consumption (approximately 1-2 cups/day) is sufficient to inhibit infection of multiple variants of SARS-CoV-2 entry, suggesting coffee could be a dietary strategy to prevent SARS-CoV2 infection. CONCLUSIONS: This study verified moderate coffee consumption, including decaffeination, can provide a new guideline for the prevention of SARS-CoV-2. Based on the results, we also suggest a coffee-drinking plan for people to prevent infection in the post-COVID-19 era.

Herbal Compounds Dauricine and Isoliensinine Impede SARS-CoV-2 Viral Entry.

Targeting viral entry has been the focal point for the last 3 years due to the continued threat posed by SARS-CoV-2. SARS-CoV-2's entry is highly dependent on the interaction between the virus's Spike protein and host receptors. The virus's Spike protein is a key modulator of viral entry, allowing sequential cleavage of ACE2 at the S1/S2 and S2 sites, resulting in the amalgamation of membranes and subsequent entry of the virus. A Polybasic insertion (PRRAR) conveniently located at the S1/S2 site can also be cleaved by furin or by serine protease, TMPRSS2, at the cell surface. Since ACE2 and TMPRSS2 are conveniently located on the surface of host cells, targeting one or both receptors may inhibit receptor-ligand interaction. Here, we show that Dauricine and Isoliensinine, two commonly used herbal compounds, were capable of inhibiting SARS-CoV-2 viral entry by reducing Spike-ACE2 interaction but not suppressing TMPRSS2 protease activity. Further, our biological assays using pseudoviruses engineered to express Spike proteins of different variants revealed a reduction in infection rates following treatment with these compounds. The molecular modeling revealed an interconnection between R403 of Spike protein and both two compounds. Spike mutations at residue R403 are critical, and often utilized by ACE2 to gain cell access. Overall, our findings strongly suggest that Dauricine and Isoliensinine are effective in blocking Spike-ACE2 interaction and may serve as effective therapeutic agents for targeting SARS-CoV-2's viral entry.

Preparation of Micron-Sized TS-1 Spherical Membrane Catalysts and Their Performance in the Epoxidation of Chloropropene.

Titanium silica (TS-1) membrane catalysts grown on the surfaces of spherical substrates can both exploit the high catalytic performance and facilitate their separation from products after the reaction. In this work, a simple static crystallization method was used to perform the in situ construction of a TS-1 membrane on the surfaces of micron-sized spherical carriers. The shortcomings of the TS-1 membrane under static crystallization conditions were overcome by in situ dynamic crystallization, and the effect of rotation speed on the formation of the molecular sieve membrane was investigated. The results showed that the molecular sieve membrane was smooth and homogeneous, with a higher synthesis efficiency at a slow rotational speed. The micron TS-1 spherical membrane catalytic chloropropene epoxidation reaction was investigated in a fixed bed, and the conversion of hydrogen peroxide and selectivity of epichlorohydrin reached 99.4 and 96.8%, respectively. After being reused twice, the catalyst still maintained a stable catalytic performance.

Photo-crosslinked adhesive hydrogel loaded with extracellular vesicles promoting hemostasis and liver regeneration.

Hepatectomy is an effective surgical method for the treatment of liver diseases, but intraoperative bleeding and postoperative liver function recovery are still key issues. This study aims to develop a composite hydrogel dressing with excellent hemostatic properties, biocompatibility, and ability to promote liver cell regeneration. The modified gelatin matrix (GelMA, 10%) was mixed with equal volumes of sodium alginate-dopamine (Alg-DA) at concentrations of 0.5%, 1%, and 2%. Then a cross-linking agent (0.1%) was added to prepare different composite hydrogels under UV light, named GelMA/Alg-DA-0.5, GelMA/Alg-DA-1 and GelMA/Alg-DA-2, respectively. All the prepared hydrogel has a porous structure with a porosity greater than 65%, and could be stabilized in a gel state after being cross-linked by ultraviolet light. Physicochemical characterization showed that the elastic modulus, water absorption, adhesion, and compressibility of the composite hydrogels were improved with increasing Alg-DA content. Furthermore, the prepared hydrogel exhibits in vitro degradability, excellent biocompatibility, and good hemostatic function. Among all tested groups, the group of GelMA/Alg-DA-1 hydrogel performed the best. To further enhance its application potential in the field of liver regeneration, adipose-derived mesenchymal stem cell exosomes (AD-MSC-Exo) were loaded into GelMA/Alg-DA-1 hydrogel. Under the same conditions, GelMA/Alg-DA-1/Exo promoted cell proliferation and migration more effectively than hydrogels without extracellular vesicles. In conclusion, the prepared GelMA/Alg-DA-1 composite hydrogel loaded with AD-MSC-Exo has great application potential in liver wound hemostasis and liver regeneration.

Atomically Dispersed Pt-Doped Co3 O4 Spinel Nanoparticles Embedded in Polyhedron Frames for Robust Propane Oxidation at Low Temperature.

This study adopts a facile and effective in situ encapsulation-oxidation strategy for constructing a coupling catalyst composed of atomically dispersed Pt-doped Co3 O4 spinel nanoparticles (NPs) embedded in polyhedron frames (PFs) for robust propane total oxidation. Benefiting from the abundant oxygen vacancies and more highly valent active Co3+ species caused by the doping of Pt atoms as well as the confinement effect, the optimized 0.2Pt-Co3 O4 NPs/PFs catalyst exhibits excellent propane catalytic activity with low T90 (184 °C), superior apparent reaction rate (21.62×108 (mol gcat -1 s-1 )), low apparent activation energy (Ea = 17.89 kJ mol-1 ), high turnover frequency ( 811×107 (mol gcat -1 s-1 )) as well as good stability. In situ diffuse reflectance infrared Fourier transform spectroscopy and density functional theory calculations indicate that the doping of Pt atoms enhances the oxygen activation ability, and decreases the energy barrier required for CH bond breaking, thus improving the deep oxidation process of the intermediate species. This study opens up new ideas for constructing coupling catalysts from atomic scale with low cost to enhance the activation of oxygen molecules and the deep oxidation of linear short chain alkanes at low temperature.

Structural insights into EphA4 unconventional activation from prediction of the EphA4 and its complex with ribonuclease 1.

It has been shown that several ribonuclease (RNase) A superfamily proteins serve as ligands of receptor tyrosine kinases (RTKs), representing a new concept for ligand/receptor interaction. Moreover, recent studies indicate high clinical values for this type of ligand/RTK interactions. However, there is no structural report for this new family of ligand/receptor. In an attempt to understand how RNase and RTK may interact, we focused on the RNase1/ephrin type-A receptor 4 (EphA4) complex and predicted their structure by using the state-of-the-art machine learning method, AlphaFold and its derivative method, AF2Complex. In this model, electrostatic force plays an essential role for the specific ligand/receptor interaction. We found the R39 of RNase1 is the key residue for EphA4-binding and activation. Mutation on this residue causes disruption of an essential basic patch, resulting in weaker ligand-receptor association and leading to the loss of activation. By comparing the surface charge distribution of the RNase A superfamily, we found the positively charged residues on the RNase1 surface is more accessible for EphA4 forming salt bridges than other RNases. Furthermore, RNase1 binds to the ligand-binding domain (LBD) of EphA4, which is responsible for the traditional ligand ephrin-binding. Our model reveals the location of RNase1 on EphA4 partially overlaps with that of ephrin-A5, a traditional ligand of EphA4, suggesting steric hindrance as the basis by which the ephrin-A5 precludes interactions of RNase1 with EphA4. Together, our discovery of RNase1/EphA4 interface provides a potential treatment strategy by blocking the RNase1-EphA4 axis.

Electron ultra-high dose rate FLASH irradiation study using a clinical linac: Linac modification, dosimetry, and radiobiological outcome.

PURPOSE: Ultra-high dose rate FLASH irradiation (FLASH-IR) has been shown to cause less normal tissue damage compared with conventional irradiation (CONV-IR), this is known as the "FLASH effect." It has attracted immense research interest because its underlying mechanism is scarcely known. The purpose of this study was to determine whether FLASH-IR and CONV-IR induce differential inflammatory cytokine expression using a modified clinical linac. MATERIALS AND METHODS: An Elekta Synergy linac was used to deliver 6 MeV CONV-IR and modified to deliver FLASH-IR. Female FvB mice were randomly assigned to three different groups: a non-irradiated control, CONV-IR, or FLASH-IR. The FLASH-IR beam was produced by single pulses repeated manually with a 20-s interval (Strategy 1), or single-trigger multiple pulses with a 10 ms interval (Strategy 2). Mice were immobilized in the prone position in a custom-designed applicator with Gafchromic films positioned under the body. The prescribed doses for the mice were 6 to 18 Gy and verified using Gafchromic films. Cytokine expression of three pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and one anti-inflammatory cytokine (IL-10) in serum samples and skin tissue were examined within 1 month post-IR. RESULTS: The modified linac delivered radiation at an intra-pulse dose rate of around 1 × 106 Gy/s and a dose per pulse over 2 Gy at a source-to-surface distance (SSD) of 13 to 15 cm. The achieved dose coverage was 90%-105% of the maximum dose within -20 to 20 mm in the X direction and 95% within -30 to 30 mm in the Y direction. The absolute deviations between the prescribed dose and the actual dose were 2.21%, 6.04%, 2.09%, and 2.73% for 6, 9, 12, and 15 Gy as measured by EBT3 films, respectively; and 4.00%, 4.49%, and 2.30% for 10, 14, and 18 Gy as measured by the EBT XD films, respectively. The reductions in the CONV-IR versus the FLASH-IR group were 4.89%, 10.28%, -7.8%, and -22.17% for TNF-α, IFN-γ, IL-6, and IL-10 in the serum on D6, respectively; 37.26%, 67.16%, 56.68%, and -18.95% in the serum on D31, respectively; and 62.67%, 35.65%, 37.75%, and -12.20% for TNF-α, IFN-γ, IL-6, and IL-10 in the skin tissue, respectively. CONCLUSIONS: Ultra-high dose rate electron FLASH caused lower pro-inflammatory cytokine levels in serum and skin tissue which might mediate differential tissue damage between FLASH-IR and CONV-IR.

Critical view of safety in laparoscopic cholecystectomy: A prospective investigation from both cognitive and executive aspects.

Background: The achievement rate of the critical view of safety during laparoscopic cholecystectomy is much lower than expected. This original study aims to investigate and analyze factors associated with a low critical view of safety achievement. Materials and Methods: We prospectively collected laparoscopic cholecystectomy videos performed from September 2, 2021, to September 19, 2021, in Sichuan Province, China. The artificial intelligence system, SurgSmart, analyzed videos under the necessary corrections undergone by expert surgeons. Also, we distributed questionnaires to surgeons and analyzed them along with surgical videos simultaneously. Results: We collected 169 laparoscopic cholecystectomy surgical videos undergone by 124 surgeons, among which 105 participants gave valid answers to the questionnaire. Excluding those who conducted the bail-out process directly, the overall critical view of safety achievement rates for non-inflammatory and inflammatory groups were 18.18% (18/99) and 9.84% (6/61), respectively. Although 80.95% (85/105) of the surgeons understood the basic concept of the critical view of safety, only 4.76% (5/105) of the respondents commanded all three criteria in an error-free way. Multivariate logistic regression results showed that an unconventional surgical workflow (OR:12.372, P < 0.001), a misunderstanding of the 2nd (OR: 8.917, P < 0.05) and 3rd (OR:8.206, P < 0.05) criterion of the critical view of safety, and the don't mistake "fundus-first technique" as one criterion of the critical view of safety (OR:0.123, P < 0.01) were associated with lower and higher achievements of the critical view of safety, respectively. Conclusions: The execution and cognition of the critical view of safety are deficient, especially the latter one. Thus, increasing the critical view of safety surgical awareness may effectively improve its achievement rate.

Interfacial Engineering of a Phase-Controlled Heterojunction for High-Efficiency HER, OER, and ORR Trifunctional Electrocatalysis.

The development of low-cost and high-performance electrocatalysts for simultaneously boosting the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) is highly crucial but still challenging. Herein, a facile one-step solid-phase polymerization and confined pyrolysis strategy is developed for scalable synthesis of a Fe x P/Fe3C-based (x = 1, 2) heterojunction with controllable iron phosphide crystal phases. By effective heterojunction interface regulation, the strong synergic effect between FeP/Fe3C and N- and P-codoped carbon (NPC) modified the electronic structure, resulting in an excellent electrocatalytic performance for the HER, OER, and ORR synchronously. Typically, the FeP/Fe3C@NPC catalyst exhibits efficient HER activity with a low overpotential of 10 mA cm-2 for the HER (97 mV) and OER (440 mV) and a high half-wave potential of 0.87 V for the ORR, as well as excellent stability in alkaline media. Theoretical calculations demonstrated that Fe3C can promote the activation of water molecules, while FeP is beneficial to the removal of H2 and the FeP/Fe3C heterojunction can facilitate both Volmer and Heyrovsky steps in the HER process simultaneously. Moreover, FeP has a stronger inhibitory effect on OH adsorption, revealing that the FeP/Fe3C heterojunction also shows a better promoting effect for both the OER and ORR, respectively.

Long noncoding RNA LINC00857 promotes pancreatic cancer proliferation and metastasis by regulating the miR-130b/RHOA axis.

Dysregulation of long noncoding RNAs (lncRNAs) is involved in the pathogenesis and progression of pancreatic cancer (PC). In the current study, we investigated the role and molecular mechanism of LINC00857 in PC. The expression of LINC00857 in PC was analyzed by bioinformatics analysis and qRT-PCR, and the relationship between LINC00857 expression and clinical characteristics of patients of PC was analyzed by Fisher's exact test. Gain- and loss-of-function assays were performed to determine the biological function of LINC00857 in PC. The relationship between LINC00857, miR-130b, and RHOA were determined by RNA pull-down assay, luciferase assay, and qRT-PCR. Our results demonstrated that LINC00857 expression was elevated in PC, and high expression of LINC00857 was positively associated with tumor diameter, T stage, and lymph node metastasis. LINC00857 promoted the proliferation and mobility of PC cells in vitro and in vivo. Mechanistically, LINC00857 acts as a sponge for miR-130b and decreases its expression. miR-130b exhibits tumor suppressor functions in PC, and RHOA was identified as the key target gene of miR-130b. The functions induced by LINC00857 in PC cells were dependent on the miR-130b/RHOA axis. In conclusion, the current study indicated that LINC00857 promotes PC tumorigenesis and metastasis by modulating the miR-130b/RHOA axis, implying that LINC00857 might be a new therapeutic target for PC.

A noncoding RNA modulator potentiates phenylalanine metabolism in mice.

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.

Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module.

The Cdk8 kinase module (CKM) in Mediator, comprising Med13, Med12, CycC, and Cdk8, regulates RNA polymerase II transcription through kinase-dependent and -independent functions. Numerous pathogenic mutations causative for neurodevelopmental disorders and cancer congregate in CKM subunits. However, the structure of the intact CKM and the mechanism by which Cdk8 is non-canonically activated and functionally affected by oncogenic CKM alterations are poorly understood. Here, we report a cryo-electron microscopy structure of Saccharomyces cerevisiae CKM that redefines prior CKM structural models and explains the mechanism of Med12-dependent Cdk8 activation. Med12 interacts extensively with CycC and activates Cdk8 by stabilizing its activation (T-)loop through conserved Med12 residues recurrently mutated in human tumors. Unexpectedly, Med13 has a characteristic Argonaute-like bi-lobal architecture. These findings not only provide a structural basis for understanding CKM function and pathological dysfunction, but also further impute a previously unknown regulatory mechanism of Mediator in transcriptional modulation through its Med13 Argonaute-like features.