Stimulus-Induced Dynamic Behavior Regulation of Flexible Crystals through the Tuning of Module Rigidity.

Introducing dynamic behavior into periodic frameworks has borne fruit in the form of flexible porous crystals. The detailed molecular design of frameworks in order to control their collective dynamics is of particular interest, for example, to achieve stimulus-induced behavior. Herein, by varying the degree of rigidity of ditopic pillar linkers, two isostructural flexible metal-organic frameworks (MOFs) with common rigid supermolecular building bilayers were constructed. The subtle substitution of single (in bibenzyl-4,4'-dicarboxylic acid; H2BBDC) with double (in 4,4'-stilbenedicarboxylic acid; H2SDC) C-C bonds in pillared linkers led to markedly different flexible behavior of these two MOFs. Upon the removal of guest molecules, both frameworks clearly show reversible single-crystal-to-single-crystal transformations involving the cis-trans conformation change and a resulting swing of the corresponding pillar linkers, which gives rise to Flex-Cd-MOF-1a and Flex-Cd-MOF-2a, respectively. Strikingly, a more favorable gas-induced dynamic behavior in Flex-Cd-MOF-2a was verified in detail by stepwise C3H6/C3H8 sorption isotherms and the corresponding in situ powder X-ray diffraction experiments. These insights are strongly supported by molecular modeling studies on the sorption mechanism that explores the sorption landscape. Furthermore, a consistency between the macroscopic elasticity and microscopic flexibility of Flex-Cd-MOF-2 was observed. This work fuels a growing interest in developing MOFs with desired chemomechanical functions and presents detailed insights into the origins of flexible MOFs.

Molecular and immunological characteristics of postoperative relapse in lymph node-positive esophageal squamous cell cancer.

BACKGROUND: The molecular and immunological characteristics of primary tumors and positive lymph nodes in esophageal squamous cell carcinoma (ESCC) are unknown and the relationship with recurrence is unclear, which this study attempted to explore. METHODS: A total of 30 ESCC patients with lymph node positive (IIB-IVA) were enrolled. Among them, primary tumor and lymph node specimens were collected from each patient, and subjected to 551-tumor-targeted DNA sequencing and 289-immuno-oncology RNA panel sequencing to identify the different molecular basis and immunological features, respectively. RESULTS: The primary tumors exhibited a higher mutation burden than lymph nodes (p < 0.001). One-year recurrent ESCC exhibited a higher Mucin16 (MUC16) mutation rate (p = 0.038), as well as univariate and multivariate analysis revealed that MUC16 mutation is independent genetic factor associated with reduced relapse-free survival (univariate, HR: 5.39, 95% CI: 1.67-17.4, p = 0.005; multivariate, HR: 7.36, 95% CI: 1.79-30.23, p = 0.006). Transcriptomic results showed non-relapse group had higher cytolytic activity (CYT) score (p = 0.025), and was enriched in the IFN-α pathway (p = 0.036), while those in the relapsed group were enriched in the TNF-α/NF-κB (p = 0.001) and PI3K/Akt pathway (p = 0.014). CONCLUSION: The difference in molecular characteristics between primary lesions and lymph nodes may be the cause of the inconsistent clinical outcomes. Mutations of MUC16 and poor immune infiltration are associated with rapid relapse of nodes-positive ESCC.

Chloroflexus aurantiacus acetyl-CoA carboxylase evolves fused biotin carboxylase and biotin carboxyl carrier protein to complete carboxylation activity.

Acetyl-CoA carboxylases (ACCs) convert acetyl-CoA to malonyl-CoA, a key step in fatty acid biosynthesis and autotrophic carbon fixation pathways. Three functionally distinct components, biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT), are either separated or partially fused in different combinations, forming heteromeric ACCs. However, an ACC with fused BC-BCCP and separate CT has not been identified, leaving its catalytic mechanism unclear. Here, we identify two BC isoforms (BC1 and BC2) from Chloroflexus aurantiacus, a filamentous anoxygenic phototroph that employs 3-hydroxypropionate (3-HP) bi-cycle rather than Calvin cycle for autotrophic carbon fixation. We reveal that BC1 possesses fused BC and BCCP domains, where BCCP could be biotinylated by E. coli or C. aurantiacus BirA on Lys553 residue. Crystal structures of BC1 and BC2 at 3.2 Å and 3.0 Å resolutions, respectively, further reveal a tetramer of two BC1-BC homodimers, and a BC2 homodimer, all exhibiting similar BC architectures. The two BC1-BC homodimers are connected by an eight-stranded ß-barrel of the partially resolved BCCP domain. Disruption of ß-barrel results in dissociation of the tetramer into dimers in solution and decreased biotin carboxylase activity. Biotinylation of the BCCP domain further promotes BC1 and CTß-CTα interactions to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-HP via co-expression with a recombinant malonyl-CoA reductase in E. coli cells. This study revealed a heteromeric ACC that evolves fused BC-BCCP but separate CTα and CTß to complete ACC activity.IMPORTANCEAcetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in fatty acid biosynthesis and autotrophic carbon fixation pathways across a wide range of organisms, making them attractive targets for drug discovery against various infections and diseases. Although structural studies on homomeric ACCs, which consist of a single protein with three subunits, have revealed the "swing domain model" where the biotin carboxyl carrier protein (BCCP) domain translocates between biotin carboxylase (BC) and carboxyltransferase (CT) active sites to facilitate the reaction, our understanding of the subunit composition and catalytic mechanism in heteromeric ACCs remains limited. Here, we identify a novel ACC from an ancient anoxygenic photosynthetic bacterium Chloroflexus aurantiacus, it evolves fused BC and BCCP domain, but separate CT components to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-hydroxypropionate (3-HP) via co-expression with recombinant malonyl-CoA reductase in E. coli cells. These findings expand the diversity and molecular evolution of heteromeric ACCs and provide a structural basis for potential applications in 3-HP biosynthesis.

Flexible sensors with zero Poisson's ratio.

Flexible sensors have been developed for the perception of various stimuli. However, complex deformation, usually resulting from forces or strains from multi-axes, can be challenging to measure due to the lack of independent perception of multiaxial stimuli. Herein, flexible sensors based on the metamaterial membrane with zero Poisson's ratio (ZPR) are proposed to achieve independent detection of biaxial stimuli. By deliberately designing the geometric dimensions and arrangement parameters of elements, the Poisson's ratio of an elastomer membrane can be modulated from negative to positive, and the ZPR membrane can maintain a constant transverse dimension under longitudinal stimuli. Due to the accurate monitoring of grasping force by ZPR sensors that are insensitive to curvatures of contact surfaces, rigid robotic manipulators can be guided to safely grasp deformable objects. Meanwhile, the ZPR sensor can also precisely distinguish different states of manipulators. When ZPR sensors are attached to a thermal-actuation soft robot, they can accurately detect the moving distance and direction. This work presents a new strategy for independent biaxial stimuli perception through the design of mechanical metamaterials, and may inspire the future development of advanced flexible sensors for healthcare, human-machine interfaces and robotic tactile sensing.

Biventricular Impairment and Ventricular Interdependence in Patients With Alcoholic Cardiomyopathy: Insights Through Cardiac Magnetic Resonance Imaging.

BACKGROUND: Alcoholic cardiomyopathy (ACM) can lead to progressive cardiac dysfunction and heart failure, but little is known about biventricular impairment and ventricular interdependence (VI) in ACM patients. PURPOSE: To use cardiac MRI to investigate biventricular impairment and VI in ACM patients. STUDY TYPE: Retrospective. POPULATION: Forty-one male patients with ACM and 45 sex- and age-matched controls. FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence, inversion recovery prepared echo-planar imaging sequence and phase-sensitive inversion recovery sequence. ASSESSMENT: Biventricular structure, function, and global strain (encompassing peak strain [PS], peak systolic, and diastolic strain rate), PS of interventricular septal (IVS), microvascular perfusion (including upslope and time to maximum signal intensity [TTM]), late gadolinium enhancement (LGE), and baseline characteristics were compared between the controls and ACM patients. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, Pearson's correlation, and multivariable linear regression models with a stepwise selection procedure. A two-tailed P value <0.05 was deemed as statistically significant. RESULTS: Compared to control subjects, ACM patients showed significantly biventricular adverse remodeling, reduced left ventricle (LV) global upslope and prolonged global TTM, and the presence of LGE. ACM patients were characterized by a significant decline in all global strain within the LV, right ventricle (RV), and IVS compared with the controls. RV global PS was significantly associated with LV global PS and IVS PS in radial, circumferential, and longitudinal directions. Multivariable analyses demonstrated the longitudinal PS of IVS was significantly correlated with RV global radial PS (ß = 0.614) and circumferential PS (ß = 0.545). Additionally, RV global longitudinal PS (GLPS) was significantly associated with radial PS of IVS (ß = -0.631) and LV GLPS (ß = 1.096). DATA CONCLUSION: ACM patients exhibited biventricular adverse structural alterations and impaired systolic and diastolic function. This cohort also showed reduced LV microvascular perfusion, the presence of LGE, and unfavorable VI. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Robust Model Watermarking for Image Processing Networks via Structure Consistency.

The intellectual property of deep networks can be easily "stolen" by surrogate model attack. There has been significant progress in protecting the model IP in classification tasks. However, little attention has been devoted to the protection of image processing models. By utilizing consistent invisible spatial watermarks, the work [1] first considered model watermarking for deep image processing networks and demonstrated its efficacy in many downstream tasks. Its success depends on the hypothesis that if a consistent watermark exists in all prediction outputs, that watermark will be learned into the attacker's surrogate model. However, when the attacker uses common data augmentation attacks (e.g., rotate, crop, and resize) during surrogate model training, it will fail because the underlying watermark consistency is destroyed. To mitigate this issue, we propose a new watermarking methodology, "structure consistency", based on which a new deep structure-aligned model watermarking algorithm is designed. Specifically, the embedded watermarks are designed to be aligned with physically consistent image structures, such as edges or semantic regions. Experiments demonstrate that our method is more robust than the baseline in resisting data augmentation attacks. Besides that, we test the generalization ability and robustness of our method to a broader range of adaptive attacks.

Effects of heated-treating temperature on the stability and electrochemical performance of alginate-based multi-crosslinked biomembranes.

In this study, the organosilane nanoparticles as additive and crosslinker were prepared and incorporated into sodium alginate to fabricate a series of alginate-based multi-crosslinked biomembranes at different thermal treatment temperature without the usage of another crosslinking agent. The effects of treatment temperature on the stability of biomembranes including dimensional, oxidative, hydrolytic and mechanical stability were investigated in detail. As a whole, the stability of biomembranes exhibited increasing tendency with the increment of treatment temperature due to the formation of more compact internal network structure. The electrochemical performance of biomembranes in respect to their potential as proton exchange membranes for direct methanol fuel cell application were also investigated based on the treatment temperature. The results revealed that the biomembranes possessed excellent methanol resistance and the methanol diffusion coefficient decreased with the increment of treatment temperature. The biomembrane with 120 °C heat-treatment showed the optimal selectivity (14.30 × 105 Ss cm-3), which was about 1.77 and 68.10 times of that and of M-80 (8.09 × 105 Ss cm-3) and Nafion@117 (0.21 × 105 Ss cm-3), respectively. Fuel cell performance measurements showed that M-120 possessed higher maximum power density and cell stability compared with M-80 and Nafion@117, indicating its best adaptability for use in direct methanol fuel cell.

Progress in Cardiac Magnetic Resonance Feature Tracking for Evaluating Myocardial Strain in Type-2 Diabetes Mellitus.

The global prevalence of type-2 diabetes mellitus (T2DM) has caused harm to human health and economies. Cardiovascular disease is one main cause of T2DM mortality. Increased prevalence of diabetes and associated heart failure (HF) is common in older populations, so accurately evaluating heart-related injury and T2DM risk factors and conducting early intervention are important. Quantitative cardiovascular system imaging assessments, including functional imaging during cardiovascular disease treatment, are also important. The left-ventricular ejection fraction (LVEF) has been traditionally used to monitor cardiac function; it is often preserved or increased in early T2DM, but subclinical heart deformation and dysfunction can occur. Myocardial strains are sensitive to global and regional heart dysfunction in subclinical T2DM. Cardiac magnetic resonance feature-tracking technology (CMR-FT) can visualize and quantify strain and identify subclinical myocardial injury for early management, especially with preserved LVEF. Meanwhile, CMR-FT can be used to evaluate the multiple cardiac chambers involvement mediated by T2DM and the coexistence of complications. This review discusses CMR-FT principles, clinical applications, and research progress in the evaluation of myocardial strain in T2DM.

Evaluating the contribution of historical and contemporary temperature to the oospore production of self-fertile Phytophthora infestans.

Reproductive systems play an important role in the ecological function of species, but little is known about how climate change, such as global warming, may affect the reproductive systems of microbes. In this study, 116 Phytophthora infestans isolates sampled from five different altitudes along a mountain were evaluated under five temperature regimes to determine the effects of historical and experimental temperature on the reproductive system of the pathogen. Both altitude, a proxy for historical pathogen adaptation to temperature, and temperature used in the experiment affected the sexual reproduction of the pathogen, with experimental temperature, that is, contemporary temperature, playing a role several times more important than historical temperature. Furthermore, the potential of sexual reproduction, measured by the number of oospores quantified, increased with the temperature breadth (i.e., difference between the highest and lowest temperature at which sexual reproduction takes place) of the pathogen and reached the maximum at the experimental temperature of 21°C, which is higher than the annual average temperature in many potato-producing areas. The results suggest that rising air temperature associated with global warming may increase the potential of sexual reproduction in P. infestans. Given the importance of sexuality in pathogenicity and ecological adaptation of pathogens, these results suggest that global warming may increase the threat of P. infestans to agricultural production and other ecological services and highlight that new epidemiological strategies may need to be implemented for future food security and ecological resilience.

Meta-analysis of the relationship between montelukast use and neuropsychiatric events in patients with allergic airway disease.

Use of montelukast, as a cause of neuropsychiatric events, in patients with asthma or allergic rhinitis is controversial, and comprehensive statistical analyses verifying this relationship remain lacking. To better understand the relationship between montelukast and neuropsychiatric events, it is vital to guide patients in the effective use of the drug, especially in children whose mothers are concerned about its side effects. In this study, randomized controlled trials (RCTs) investigating montelukast and neuropsychiatric events were retrieved from a literature search of the Medline (1966 to February 2023), Embase (1974 to February 2023), Web of Science, and other related databases. After screening, 18 RCTs were ultimately included in a meta-analysis to merge statistics, which demonstrated no significant increase in neuropsychiatric events compared with placebo. A similar pattern of adverse neuropsychiatric events was observed in patients grouped according to age, with headache being the most common adverse neuropsychiatric event. Overall, montelukast did not significantly increase neuropsychiatric events in patients with allergic rhinitis and/or asthma compared with placebo. Large-sample RCTs are needed to verify the association between neuropsychiatric events and montelukast use in children, and attention is also devoted to FDA warnings.

Highly Stable Amide-Functionalized Zirconium-Organic Frameworks: Synthesis, Structure, and Methane Storage Capacity.

With the development of crystalline porous materials toward methane storage, the stability issue of metal-organic framework (MOF) materials has caused great concern despite high working capacity. Considering the high stability of zirconium-based MOFs and effective functions of amide groups toward gas adsorption, herein, a series of UiO-66 type of Zr-MOFs, namely, Zr-fcu-H/F/CH3/OH, were successfully designed and synthesized by virtue of amide-functionalized dicarboxylate ligands bearing distinct side groups (i.e., -H, -F, -CH3, and -OH) and ZrCl4 in the presence of trifluoroacetic acid as the modulator. Single-crystal X-ray diffraction and topology analyses reveal that these compounds are archetypal fcu MOFs encompassing octahedral and tetrahedral cages, respectively. The N2 sorption isotherms and acid-base stability tests demonstrate that the materials possess not only relatively high surface areas, pore volumes, and appropriate pore sizes but also great hydrolytic stabilities ranging pH = 3-11. Furthermore, the volumetric methane storage working capacities of Zr-fcu-H, Zr-fcu-F, Zr-fcu-CH3, and Zr-fcu-OH at 298/273 K and 80 bar are 187/217, 175/193, 167/187, and 154/171 cm3 (STP) cm-3, respectively, which indicate that the zirconium-based crystalline porous materials are capable of storing relatively high amounts of methane.

Studying positional changes of the disc-condyle-fossa complex in ADDWoR patients after TMJ disc repositioning surgery.

OBJETIVES: To investigate the positional changes in the temporomandibular joint (TMJ) disc-condyle-fossa complex of patients with anterior disc displacement without reduction (ADDWoR) and to evaluate the effect of disc repositioning (DR) surgery. MATERIAL AND METHODS: Fifteen patients with unilateral ADDWoR (30 joints) were included. MRI of the TMJ was performed at T0 (1 week before surgery), T1 (1 month after surgery), and T2 (9-12 months after surgery). The glenoid fossa, disc, and condyle were reconstructed and analyzed using Mimics software. RESULTS: In the patients with unilateral ADDWoR, the disc on the ADD side showed a tendency to downward shift in the coronal direction and forward shift in the sagittal direction; the condyle of ADD side showed a tendency to backward shift in the sagittal direction and upward shift in the coronal direction. When comparing the same ADDwoR TMJ at T0, T1, and T2, the disc was found to move upward and backward after DR surgery at T1 and T2, and the condyle was found to move upward and backward after DR surgery at T1 but returned to the original position at T2. CONCLUSIONS: ADDWoR leads to forward and downward displacement of the disc relative to the condyle and upward displacement of the condyle relative to the tuberosity. DR surgery improved upon the structural abnormalities of the TMJ complex, for which stability was maintained as determined in the 9 to 12 month postoperative follow-up. CLINIC RELEVANCE: DR surgery effectively and constantly improves the positional abnormalities of the TMJ complex.

Right-Left Ventricular Interdependence in Repaired Tetralogy of Fallot Patients With Right Ventricular Heart Failure.

BACKGROUND: Patients with repaired tetralogy of Fallot (rTOF) continue to face a heightened risk of deteriorating cardiac function, and quantitative techniques of cardiac MRI-derived cardiac structure and function provide an opportunity to explore the causes and mechanisms of cardiac deterioration. PURPOSE: To explore right-left ventricular interdependence in rTOF patients before and after the onset of right ventricular (RV) heart failure. STUDY TYPE: Retrospective. POPULATION: One hundred eighteen rTOF patients (21.85 [16.74, 29.20] years, 58 females) and 34 controls (23.5 [21, 26.5] years, 17 females) that underwent cardiac MRI were analyzed, with rTOF patients being further subdivided into those with preserved RV function (N = 54) and those that experienced RV heart failure (N = 64). FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: RV, left ventricular (LV), and septal strain; RV and LV volume. STATISTICAL TESTS: Chi-squared tests or Fisher's exact test, One-way ANOVAs with Bonferroni's post hoc test, Pearson/Spearman correlation, and multivariate backward linear regression analysis. A two-tailed P < 0.05 was deemed as the significance threshold. RESULTS: The MRI-derived RV, LV, and septal strain decreased sequentially in controls, patients with preserved RV function, and patients with RV heart failure, with a good intra-observer (0.909-0.964) and inter-observer (0.879-0.937) agreement. Correlations between LV and RV strain were found to change sequentially with RV function and were the closest in rTOF patients with RV heart failure (r = -0.270 to 0.506). Correlations between RV volume and septal strain was variable in controls (r = 0.483 to -0.604), patients with preserved RV function (r = -0.034 to -0.295), and patients with RV heart failure (r = -0.026 to 0.500). Multivariate analyses revealed that the RV longitudinal strain was independently correlated with LV strain in three directions in rTOF patients with RV heart failure (Radial -0.70 [-1.33, -0.06]; Circumferential 0.44 [0.17, 0.72]; Longitudinal 0.54 [0.26, 0.81]). DATA CONCLUSION: In rTOF patients, the coupling between RV volume and septal strain was broken during RV function compensation, and the adverse effect of RV on LV deformation was highest in patients with RV heart failure. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Biventricular Dysfunction and Ventricular Interdependence in Patients With Pulmonary Hypertension: A 3.0-T Cardiac MRI Feature Tracking Study.

BACKGROUND: Pulmonary hypertension (PH) results in right ventricular (RV) dysfunction, subsequently leading to left ventricular (LV) impairment. The mechanism underlying ventricular interdependence is largely uninvestigated. PURPOSE: To explore the biventricular dysfunction and the ventricular interdependence in PH patients. STUDY TYPE: Retrospective. POPULATION: One hundred and seven PH patients (mean pulmonary artery pressure >20 mmHg) and 72 age- and sex-matched controls with cardiac magnetic resonance imaging (MRI) studies. FIELD STRENGTH/SEQUENCE: 3.0 T/balanced steady-state free precession sequence. ASSESSMENT: LV and RV ejection fractions (EF) and RV and LV radial, circumferential, and longitudinal strains were assessed using commercial software. Strains were compared between controls, PH patients with preserved RVEF (RVEF ≥40%, N = 48), and PH patients with reduced RVEF (RVEF <40%, N = 59). STATISTICAL TESTS: Chi-squared tests or Fisher's exact test, t tests or Mann-Whitney U test, one-way ANOVA with Bonferroni's post hoc correction or Kruskal-Wallis test, Pearson or Spearman correlation, and multivariable linear regression analysis. A two-tailed P < 0.05 was deemed statistically significant. RESULTS: RV strain decreased sequentially from controls, through PH with preserved RVEF, to PH with reduced RVEF. PH patients with reduced RVEF had significantly lower LV strain, especially septal strain, and LV peak diastolic strain rate compared with both controls and PH patients with preserved RVEF. Multivariable analyses showed that RVEF was independently correlated with LV strain; furthermore, independent of RVEF, RV strain was significantly correlated with LV strain (LVGRS: ß = 0.416; LVGCS: ß = -0.371; LVGLS: ß = 0.283). DATA CONCLUSION: Subclinical impairment of RV function was found in PH with preserved RVEF. LV strain was impaired when RV was dysfunctional, which was associated with worsening RV strain. Therefore, while focusing on improving RV function, LV dysfunction in PH patients should also be monitored and treated early in order to slow the progression of the disease. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Polynuclear Rare-Earth Cluster-Directed Self-Assembly of Highly Porous Zeolite-like Metal-Organic Frameworks with Methane Storage Property.

Due to their intrinsic structural features, the design and synthesis of a new type of zeolite-like metal-organic frameworks (ZMOFs) is highly desirable but challenging. Herein, solvothermal reactions between an angular dicarboxylate linker and rare-earth (RE) ions afforded two RE-MOFs, namely, Tb-ZMOF-2 and Tb-ZMOF-3, respectively. Structural analyses reveal that Tb-ZMOF-2 encompasses a novel [446482] cage, while Tb-ZMOF-3 contains nonanuclear (i.e., D6R) and hexanuclear (i.e., D4R) RE clusters simultaneously, subsequently resulting in two new zeolitic topologies. Thanks to its high surface area and pore volume, Tb-ZMOF-2 demonstrates considerably high gravimetric and volumetric methane storage working capacities.

Heterogeneous Characteristics of the CD90+ Progenitors in the Fibrocartilage of Different Joints.

OBJECTIVE: This study aimed to isolate and compare the mesenchymal stem cell characteristics of CD90+ cells from different fibrocartilage tissues in the temporomandibular joint (TMJ), the knee joint, and the intervertebral joint to further understand the similarities and differences of these 4 fibrocartilage tissues. METHODS: CD90+ cells were isolated from TMJ disc, condylar cartilage, meniscus, and intervertebral disc by using magnetic-activated cell sorting. Cellular assays including 4.5-ethynyl-2'-deoxyuridine labeling, multilineage differentiation, colony formation, and cell migration were conducted to compare their mesenchymal stem cell characteristics. Immunofluorescent staining was performed for observing the expression of actively proliferating CD90+ cells within the tissues. H&E staining and Safranine O staining were used to compare the histological features. RESULTS: The CD90+ cells derived from these 4 fibrocartilage tissues exhibited comparable cell proliferation abilities. However, the cells from the TMJ disc displayed limited multilineage differentiation potential, colony formation, and cell migration abilities in comparison with the cells from the other fibrocartilage tissues. In vivo, there was relatively more abundant expression of CD90+ cells in the TMJ disc during the early postnatal stage. The limited EDU+ cell numbers signified a low proliferation capacity of CD90+ cells in the TMJ disc. In addition, we observed a significant decrease in cell density and a restriction in the synthesis of extracellular proteoglycans in the TMJ disc. CONCLUSION: Our study highlights the spatial heterogeneity of CD90+ cells in the fibrocartilages of different joint tissues, which may contribute to the limited cartilage repair capacity in the TMJ disc.

Targeting hnRNPC suppresses thyroid follicular epithelial cell apoptosis and necroptosis through m6A-modified ATF4 in autoimmune thyroid disease.

Both environmental and genetic factors contribute to the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). However, the exact pathogenesis and interactions that occur between environmental factors and genes remain unclear, and therapeutic targets require further investigation due to limited therapeutic options. To solve such problems, this study utilized single-cell transcriptome, whole transcriptome, full-length transcriptome (Oxford nanopore technology), and metabolome sequencing to examine thyroid lesion tissues from 2 HT patients and 2 GD patients as well as healthy thyroid tissue from 1 control subject. HT patients had increased ATF4-positive thyroid follicular epithelial (ThyFoEp) cells, which significantly increased endoplasmic reticulum stress. The enhanced sustained stress resulted in cell death mainly including apoptosis and necroptosis. The ATF4-based global gene regulatory network and experimental validation revealed that N6-methyladenosine (m6A) reader hnRNPC promoted the transcriptional activity, synthesis, and translation of ATF4 through mediating m6A modification of ATF4. Increased ATF4 expression initiated endoplasmic reticulum stress signaling, which when sustained, caused apoptosis and necroptosis in ThyFoEp cells, and mediated HT development. Targeting hnRNPC and ATF4 notably decreased ThyFoEp cell death, thus ameliorating disease progression. Collectively, this study reveals the mechanisms by which microenvironmental cells in HT and GD patients trigger and amplify the thyroid autoimmune cascade response. Furthermore, we identify new therapeutic targets for the treatment of autoimmune thyroid disease, hoping to provide a potential way for targeted therapy.

Divergent chondro/osteogenic transduction laws of fibrocartilage stem cell drive temporomandibular joint osteoarthritis in growing mice.

The anterior disc displacement (ADD) leads to temporomandibular joint osteoarthritis (TMJOA) and mandibular growth retardation in adolescents. To investigate the potential functional role of fibrocartilage stem cells (FCSCs) during the process, a surgical ADD-TMJOA mouse model was established. From 1 week after model generation, ADD mice exhibited aggravated mandibular growth retardation with osteoarthritis (OA)-like joint cartilage degeneration, manifesting with impaired chondrogenic differentiation and loss of subchondral bone homeostasis. Lineage tracing using Gli1-CreER+; Tmfl/-mice and Sox9-CreER+;Tmfl/-mice showed that ADD interfered with the chondrogenic capacity of Gli1+ FCSCs as well as osteogenic differentiation of Sox9+ lineage, mainly in the middle zone of TMJ cartilage. Then, a surgically induced disc reposition (DR) mouse model was generated. The inhibited FCSCs capacity was significantly alleviated by DR treatment in ADD mice. And both the ADD mice and adolescent ADD patients had significantly relieved OA phenotype and improved condylar growth after DR treatment. In conclusion, ADD-TMJOA leads to impaired chondrogenic progenitor capacity and osteogenesis differentiation of FCSCs lineage, resulting in cartilage degeneration and loss of subchondral bone homeostasis, finally causing TMJ growth retardation. DR at an early stage could significantly alleviate cartilage degeneration and restore TMJ cartilage growth potential.

A Multi-Task Fusion Strategy-Based Decision-Making and Planning Method for Autonomous Driving Vehicles.

The autonomous driving technology based on deep reinforcement learning (DRL) has been confirmed as one of the most cutting-edge research fields worldwide. The agent is enabled to achieve the goal of making independent decisions by interacting with the environment and learning driving strategies based on the feedback from the environment. This technology has been widely used in end-to-end driving tasks. However, this field faces several challenges. First, developing real vehicles is expensive, time-consuming, and risky. To further expedite the testing, verification, and iteration of end-to-end deep reinforcement learning algorithms, a joint simulation development and validation platform was designed and implemented in this study based on VTD-CarSim and the Tensorflow deep learning framework, and research work was conducted based on this platform. Second, sparse reward signals can cause problems (e.g., a low-sample learning rate). It is imperative for the agent to be capable of navigating in an unfamiliar environment and driving safely under a wide variety of weather or lighting conditions. To address the problem of poor generalization ability of the agent to unknown scenarios, a deep deterministic policy gradient (DDPG) decision-making and planning method was proposed in this study in accordance with a multi-task fusion strategy. The main task based on DRL decision-making planning and the auxiliary task based on image semantic segmentation were cross-fused, and part of the network was shared with the main task to reduce the possibility of model overfitting and improve the generalization ability. As indicated by the experimental results, first, the joint simulation development and validation platform built in this study exhibited prominent versatility. Users were enabled to easily substitute any default module with customized algorithms and verify the effectiveness of new functions in enhancing overall performance using other default modules of the platform. Second, the deep reinforcement learning strategy based on multi-task fusion proposed in this study was competitive. Its performance was better than other DRL algorithms in certain tasks, which improved the generalization ability of the vehicle decision-making planning algorithm.

Natural Wood-Derived Macroporous Cellulose for Highly Efficient and Ultrafast Elimination of Double-Stranded RNA from In Vitro-Transcribed mRNA.

Double-stranded RNA (dsRNA) is a major impurity that can induce innate immune responses and cause adverse drug reactions. Removing dsRNA is an essential and non-trivial process in manufacturing mRNA. Current methods for dsRNA elimination use either high-performance liquid chromatography or microcrystalline cellulose, rendering the process complex, expensive, toxic, and/or time-consuming. This study introduces a highly efficient and ultrafast method for dsRNA elimination using natural wood-derived macroporous cellulose (WMC). With a naturally formed large total pore area and low tortuosity, WMC removes up to 98% dsRNA within 5 min. This significantly shortens the time for mRNA purification and improves purification efficiency. WMC can also be filled into chromatographic columns of different sizes and integrates with fast-protein liquid chromatography for large-scale mRNA purification to meet the requirements of mRNA manufacture. This study further shows that WMC purification improves the enhanced green fluorescent protein mRNA expression efficiency by over 28% and significantly reduces cytokine secretion and innate immune responses in the cells. Successfully applying WMC provides an ultrafast and efficient platform for mRNA purification, enabling large-scale production with significant cost reduction.