S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.

Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.

Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.

Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism is highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome-related protein Spartin activates and recruits HECT-type E3 Itch to lipid droplets (LDs) to regulate their turnover. In this study, we find that Spartin promotes the formation of Itch condensates independent of LDs. Spartin activates Itch through its multiple PPAY-motif platform generated by self-oligomerization, which targets the WW12 domains of Itch and releases the autoinhibition of the ligase. Spartin-induced activation and subsequent autoubiquitination of Itch lead to liquid-liquid phase separation (LLPS) of the poly-, but not oligo-, ubiquitinated Itch together with Spartin and E2 both in vitro and in living cells. LLPS-mediated condensation of the reaction components further accelerates the generation of polyubiquitin chains, thus forming a positive feedback loop. Such Itch-Spartin condensates actively promote the autophagy-dependent turnover of LDs. Moreover, we show that the catalytic HECT domain of Itch is sufficient to interact and phase separate with poly-, but not oligo-ubiquitin chains. HECT domains from other HECT E3 ligases also exhibit LLPS-mediated the promotion of ligase activity. Therefore, LLPS and ubiquitination are mutually interdependent and LLPS promotes the ligase activity of the HECT family E3 ligases.

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer.

Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth.

Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is "hijacked" to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.

Clinical and electromyographic signals analysis about the effect of space-adjustment splint on overerupted maxillary molars.

BACKGROUND: Overerupted maxillary molars is common in adults, which can lead to insufficient intermaxillary vertical space ,great difficulty in prosthetic reconstruction ,and cause occlusal interference in movements.To reconstruct occlusal function, it is necessary to prepare enough space for prostheses. The aim of the present study was to evaluate the effect of space-adjustment occlusal splint on overerupted maxillary molars by clinical and electromyographic signals analysis. METHODS: Eighteen patients with overerupted maxillary molars were selected to wear space-adjustment occlusal splint suppressing overerupted maxillary molars for three months. Satisfaction was assessed by 5-point Likert; intermaxillary vertical space and the teeth transportation distance were measured in models; clinical periodontal status were evaluated by periodontal probing depth (PPT) and bleeding index (BI); electromyographic recordings of the masseter and anterior temporal muscles were monitored by Cranio-Mandibular K7 Evaluation System. RESULTS: All the patients were satisfied with the treatment effect (Likert scale ≧ 4). The intermaxillary space in edentulous areas after treatment showed statistically significant increasing when compared with those before treatment. PPT and BI showed no significant difference. No statistically significant differences were found in electromyographic activity of anterior temporal muscles, while a reduction of muscle activity in masseter in the contralateral side were detected in post-treatment evaluations compared with pre-treatment at mandibular rest position. CONCLUSIONS: Space-adjustment occlusal splint is an efficient treatment option on overerupted maxillary molars by intruding the maxillary molar to obtain adequate intermaxillary space for prostheses.

A Non-Canonical Function of Gß as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation.

G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, ß, and γ subunits (Gαßγ). Here, we report that G protein ß subunits (Gß) bind to DDB1 and that Gß2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gß2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gß protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling.

Entropy-controlled cross-linking in linker-mediated vitrimers.

Recently developed linker-mediated vitrimers based on metathesis of dioxaborolanes with various commercially available polymers have shown both good processability and outstanding performance, such as mechanical, thermal, and chemical resistance, suggesting new ways of processing cross-linked polymers in industry, of which the design principle remains unknown [M. Röttger et al., Science 356, 62-65 (2017)]. Here we formulate a theoretical framework to elucidate the phase behavior of the linker-mediated vitrimers, in which entropy plays a governing role. We find that, with increasing the linker concentration, vitrimers undergo a reentrant gel-sol transition, which explains a recent experiment [S. Wu, H. Yang, S. Huang, Q. Chen, Macromolecules 53, 1180-1190 (2020)]. More intriguingly, at the low temperature limit, the linker concentration still determines the cross-linking degree of the vitrimers, which originates from the competition between the conformational entropy of polymers and the translational entropy of linkers. Our theoretical predictions agree quantitatively with computer simulations, and offer guidelines in understanding and controlling the properties of this newly developed vitrimer system.

Clinical Application Value of left Ventricular Pressure-Strain Loop Examination of Myocardial Dysfunction in Patients with Hypertension at Various Risk Levels.

Objective: This study aims to determine the variations in myocardial work among patients with essential hypertension at varying risk levels by analyzing the left ventricular pressure-strain loop. Additionally, this research aims to investigate the potential diagnostic significance of myocardial work parameters in identifying myocardial dysfunction in patients with essential hypertension. Methods: We conducted a study with 79 patients who have essential hypertension and 30 healthy adults. The essential hypertension patients were categorized according to their risk level, with 10 patients in the low-risk group, 11 in the medium-risk group, 23 in the high-risk group, and 35 in the very high-risk group. We included 30 healthy adults in the study as a control group. Clinical data such as height, weight, and blood pressure were collected for all groups. Routine echocardiographic dynamic images were collected, and speck tracking echocardiography was performed to analyze global longitudinal strain and myocardial work parameters were detected by the left ventricular pressure-strain loop. Finally, the global work index, global constructive work, global wasted work, global work efficiency, and global longitudinal strain were calculated and compared among groups. The correlation between blood pressure and myocardial work parameters was analyzed. Results: Compared with the control group, inter-ventricular septum thickness was thickened in the medium-risk groups, high-risk groups,and very high-risk groups, P < .001). There was a negative linear correlation between global work efficiency and blood pressure (systolic and diastolic, and a positive linear correlation was observed between blood pressure and global work index, global constructive work, and global wasted work. Conclusion: Left ventricular pressure-strain loop can be used to evaluate changes in left ventricular myocardial work of essential hypertension patients in the early stage and with different risk stratifications.

Neuromuscular and occlusion analysis to evaluate the efficacy of three splints on patients with bruxism.

OBJECTIVE: Occlusal splints are always applied on individuals with bruxism to reduce tooth wear and relieve orofacial symptoms such as myofascial pain. The stomatognathic system is mainly composed of tooth, occlusion, masticatory muscles, and temporomandibular joint. The occlusion and masticatory muscles function are regarded as the important parameters for evaluating the stomatognathic system state objectively. However, the effects of occlusal splints on individuals with bruxism is rarely elucidated from accurate neuromuscular analysis and occlusion evaluation. The aim of the present study was to estimate the effects of three different splints (two clinically common full coverage occlusal splint and an modified anterior splint) on subjects with bruxism using K7-J5 neuromuscular analysis system and Dental Prescale II (DP2) to evaluate occlusion. METHODS: Sixteen subjects claimed to be suffering from nocturnal bruxism,with complete dentition and stable occlusal relationship, were selected for study.The intermaxillary space and the baselines of EMG-activity of the anterior temporalis and masseter were recorded for all the subjects. The participants was treated with three different splints, and outcomes were estimated by comfort index, occlusion and surface electromyography of anterior temporalis and masseter. RESULTS: At teeth clenched position, EMG data were significantly lower in the participants with use of modified anterior splint than with hard, soft occlusal splint or without splint (p < 0.05). The maximum bite force and bite area occur in subjects without use of splint, while the minimal occur in subjects with use of modified anterior splint. Intermaxillary space increased and masticatory muscles presented significant reduction of EMG data at rest position as a result of J5 (p < 0.05). CONCLUSION: Modified anterior splint seems to be more comfortable and effective in reducing occlusion force and electromyographic activity of anterior temporalis and masseter for subjects with bruxism.

Duality, Hidden Symmetry, and Dynamic Isomerism in 2D Hinge Structures.

Recently, a new type of duality was reported in some deformable mechanical networks that exhibit Kramers-like degeneracy in phononic spectrum at the self-dual point. In this work, we clarify the origin of this duality and propose a design principle of 2D self-dual structures with arbitrary complexity. We find that this duality originates from the partial central inversion (PCI) symmetry of the hinge, which belongs to a more general end-fixed scaling transformation. This symmetry gives the structure an extra degree of freedom without modifying its dynamics. This results in dynamic isomers, i.e., dissimilar 2D mechanical structures, either periodic or aperiodic, having identical dynamic modes, based on which we demonstrate a new type of wave guide without reflection or loss. Moreover, the PCI symmetry allows us to design various 2D periodic isostatic networks with hinge duality. At last, by further studying a 2D nonmechanical magnonic system, we show that the duality and the associated hidden symmetry should exist in a broad range of Hamiltonian systems.

Facilitated dynamics of an active polymer in 2D crowded environments with obstacles.

Understanding the behaviors of a single active chain in complex environments is not only an interesting topic in non-equilibrium physics but also has applicative implications in biological/medical engineering. In this work, by using molecular simulations, we systematically study the dynamical and conformational behaviors of an active polymer in crowded environments, i.e., a single active chain confined in 2D space with randomly arranged obstacles. We found that the competition between the chain's activity and rigidity in the presence of obstacles leads to many interesting dynamical and conformational states, such as the diffusive expanded state, the diffusive collapsed state, and the localized collapsed state. Importantly, we found a counter-intuitive phenomenon, i.e., crowded environments facilitate the diffusion of the active polymer within a large parameter space. As the crowdedness (packing fraction of obstacles) increases, the parameter space in which crowding-enhanced diffusion occurs still remains. This abnormal dynamics is attributed to a structural reason that the obstacles prevent active chains from collapsing. Our findings capture some generic features of active polymers in complex environments and provide insights into the design of novel drug delivery systems.

Hydrodynamics of random-organizing hyperuniform fluids.

Disordered hyperuniform structures are locally random while uniform like crystals at large length scales. Recently, an exotic hyperuniform fluid state was found in several nonequilibrium systems, while the underlying physics remains unknown. In this work, we propose a nonequilibrium (driven-dissipative) hard-sphere model and formulate a hydrodynamic theory based on Navier-Stokes equations to uncover the general mechanism of the fluidic hyperuniformity (HU). At a fixed density, this model system undergoes a smooth transition from an absorbing state to an active hyperuniform fluid and then, to the equilibrium fluid by changing the dissipation strength. We study the criticality of the absorbing-phase transition. We find that the origin of fluidic HU can be understood as the damping of a stochastic harmonic oscillator in q space, which indicates that the suppressed long-wavelength density fluctuation in the hyperuniform fluid can exhibit as either acoustic (resonance) mode or diffusive (overdamped) mode. Importantly, our theory reveals that the damping dissipation and active reciprocal interaction (driving) are the two ingredients for fluidic HU. Based on this principle, we further demonstrate how to realize the fluidic HU in an experimentally accessible active spinner system and discuss the possible realization in other systems.

Metabolite sensing and signaling in cancer.

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.

Effect of inorganic phosphate on migration and osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: Phosphate is the major ingredient of bone tissue, and is also an important component of commercial bone substitute materials, bone scaffolds, and implant surface coatings. With the dissolution of the bone substitute materials and the degradation by cells, local ion concentrations will change and affect bone tissue reconstruction. Bone marrow -derived mesenchymal stem cells (BM-MSCs) are main autologous cells to repair injured bone. When bone injure occurs, BM-MSCs migrate to the damaged area, differentiate into osteoblasts, and secrete bioactive factors to promote bone tissue repaired. This study aimed to investigate the effect of inorganic phosphate (Pi) at a series of concentration on migration and osteogenic differentiation of human bone marrow -derived mesenchymal stem cells(hBM-MSCs). METHODS: The culture of hBM-MSCs in mediums with different concentration of Pi from 2 mM to 10 mM were performed. HBM-MSCs migration were examined with transwell assays. HBM-MSCs proliferation were evaluated by cell counting kit-8 colorimetric method. Osteogenic genes expression were analyzed by real-time reverse transcriptase polymerase chain reaction. Mineralized nodules formation were demonstrated by Alizarin red staining. RESULT: 4-10 mM Pi could effectively promote the migration of hBM-MSCs at 12 h and 18 h. There was no significant difference in the migration number of hBM-MSCs in Pi culture mediums at a concentration of 6, 8, and10mM. 2-10 mM Pi could promote the proliferation of hBM-MSCs to varying degrees in the observation period, while 4-10 mM Pi could promote the osteogenic differentiation and mineralization of hBM-MSCs. CONCLUSION: The findings in our study showed 4-10 mM Pi could promote the migration, osteogenic differentiation, and mineralization of hBM-MSCs.

Self-Assembly of Isostatic Self-Dual Colloidal Crystals.

Self-dual structures whose dual counterparts are themselves possess unique hidden symmetry, beyond the description of classical spatial symmetry groups. Here we propose a strategy based on a nematic monolayer of attractive half-cylindrical colloids to self-assemble these exotic structures. This system can be seen as a 2D system of semidisks. By using Monte Carlo simulations, we discover two isostatic self-dual crystals, i.e., an unreported crystal with pmg space-group symmetry and the twisted kagome crystal. For the pmg crystal approaching the critical point, we find the double degeneracy of the full phononic spectrum at the self-dual point and the merging of two tilted Weyl nodes into one critically tilted Dirac node. The latter is "accidentally" located on the high-symmetry line. The formation of this unconventional Dirac node is due to the emergence of the critical flatbands at the self-dual point, which are linear combinations of "finite-frequency" floppy modes. These modes can be understood as mechanically coupled self-dual rhombus chains vibrating in some unique uncoupled ways. Our work paves the way for designing and fabricating self-dual materials with exotic mechanical or phononic properties.

Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.

Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.

Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization.

Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylation-mimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.

Supercrystallographic Reconstruction of 3D Nanorod Assembly with Collectively Anisotropic Upconversion Fluorescence.

Constructing three-dimensional (3D) metamaterials from functional nanoparticles endows them with emerging collective properties tailored by the packing geometries. Herein, we report 3D supercrystals self-assembled from upconversion nanorods (NaYF4:Yb,Er NRs), which exhibit both translational ordering of NRs and orientational ordering between constituent NRs in the superlattice (SL). The construction of 3D reciprocal space mappings (RSMs) based on synchrotron-based X-ray scattering measurements was developed to uncover the complex structure of such an assembly. That is, the two main orthogonal sets of hexagonal close-packing (hcp)-like SLs share the [110]SL axis, and NRs within the SL possess orientational relationships of [120]NR//[100]SL, [210]NR//[010]SL, and [001]NR//[001]SL. Notably, these supercrystals containing well-aligned NRs exhibit collectively anisotropic upconversion fluorescence in two perpendicular directions. This study not only demonstrates novel crystalline superstructures and functionality of NR-based 3D assemblies but also offers a unique tool for deciphering a wide range of complex nanoparticle supercrystals.

[A Review of Metabolic Stress and Development of Pancreatic Cancer].

Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious malignancies with a 5-year survival rate of less than 8%. Therefore, it is crucial to investigate the molecular mechanism underlining PDAC initiation, promotion, and progression for efficient treatment of PDAC. In order to adapt and survive in an extremely adverse microenvironment of hypoxia and insufficiency of nutrients and energy, PDAC cells undergo extensive metabolic modification triggered by intrinsic signalings which are activated by different genetic events, including mutations occurred at K RAS, TP53, and DPC4/ SMAD4, collaboratively promoting PDAC development. Notably, PDCA cells have extensive crosstalk in the form of reciprocal metabolic flux with its surrounding microenvironment to facilitate tumor advancement and therapy resistance. We herein summarize recent findings of PDAC metabolism and discuss metabolic rewiring-based therapeutic strategies.