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"Gu, Ye"
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Malfunction of airway basal stem cells plays a crucial role in pathophysiology of tracheobronchopathia osteoplastica
Understanding disease-associated stem cell abnormality has major clinical implications for prevention and treatment of human disorders, as well as for regenerative medicine. Here we report a multifaceted study on airway epithelial stem cells in Tracheobronchopathia Osteochondroplastica (TO), an under-detected tracheobronchial disorder of unknown etiology and lack of specific treatment. Epithelial squamous metaplasia and heterotopic bone formation with abnormal cartilage proliferation and calcium deposits are key pathological hallmarks of this disorder, but it is unknown whether they are coincident or share certain pathogenic mechanisms in common. By functional evaluation and genome-wide profiling at both transcriptional and epigenetic levels, we reveal a role of airway basal cells in TO progression by acting as a repository of inflammatory and TGFβ-BMP signals, which contributes to both epithelial metaplasia and mesenchymal osteo-chondrogenesis via extracellular signaling and matrix remodeling. Restoration of microenvironment by cell correction or local pathway intervention may provide therapeutic benefits.
Tracheobronchopathia osteoplastica (TO), is an underreported affliction characterized by squamous metaplasia and heterotopic bone formation in trachea and bronchi. Here the authors apply functional, as well as genome-wide transcriptional and epigenetic profiling to identify airway basal cells dysfunction underlying TO.
Journal Article
Next-generation vaccines against bacterial pathogens: mRNA and beyond
The global rise of multidrug-resistant (MDR) bacterial infections has exacerbated the need for effective vaccines to prevent these hard-to-treat pathogens. Traditional vaccine approaches have achieved tremendous successes but often fall short for pathogens like
(TB), which evades host immunity through complex mechanisms, and for multidrug-resistant ESKAPE bacteria, where antibiotic resistance and antigenic variability complicate effective vaccine development. The COVID-19 pandemic spurred unprecedented advances in vaccine technology - particularly mRNA vaccines - reviving interest in novel platforms for bacterial diseases. Here we review next-generation vaccine strategies, focusing on nucleic acid-based platforms such as mRNA, DNA, and self-amplifying RNA (saRNA), as well as viral vector vaccines. We also examine nanoparticle technologies that serve as delivery systems or adjuvant platforms across these approaches. We discuss the unique opportunities of mRNA vaccines to induce both robust antibody and T-cell responses required for intracellular infections like TB, as well as the challenges of antigen discovery and delivery (e.g. lipid nanoparticles). Each platform's mechanism, immunogenic profile, current development status, and challenges are analyzed, including comparative insights. We highlight recent progress such as mRNA vaccine candidates against TB entering clinical trials and saRNA prototypes protecting against plague in animals. Finally, we provide a perspective on the future of vaccine strategies to combat antimicrobial resistance (AMR) - emphasizing the integration of multiple platforms, global collaborative efforts, regulatory pathways, and the translational hurdles that must be overcome to bring these next-generation vaccines from bench to bedside.
Journal Article
The diagnostic performance of endobronchial ultrasound with Xpert MTB/RIF Ultra in smear-negative pulmonary tuberculosis
Objective
This study investigated the diagnostic performance of endobronchial ultrasound with Xpert MTB/RIF Ultra (Ultra) for detecting smear-negative pulmonary tuberculosis (TB).
Methods
143 patients suspected of sputum smear-negative pulmonary tuberculosis were enrolled in this study in Shanghai Pulmonary Hospital, China. These patients underwent endobronchial ultrasound with a guide sheath (EBUS-GS) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) based on their chest CT manifestations. We assessed the sensitivity and specificity of tissue specimens with Ultra in the TB group and non-TB group. Culture and clinical diagnosis were used as gold-standard for TB.
Results
Among these 143 patients, 11 patients were culture-positive TB, 85 patients were diagnosed with culture-negative TB and 47 were with the non-TB diseases. Direct testing with microscopy (Acid-Fast Bacilli smear, AFB), liquid culture, pathology, Xpert MTB/RIF(Xpert) test and Ultra had a sensitivity of 8.3%, 11.5%, 42.7%, 64.6%, and 78.1% individually among all the TB patients. Ultra had a higher sensitivity than Xpert (
P
= 0.011). But Ultra had a specificity of 59.6% (95% CI 44.3–73.3), lower than that of Xpert (89.4%, 95% CI 76.1–96.0,
P
= 0.001). Ultra had the same sensitivity on specimens from EBUS-TBNA and EBUS-GS (
P
= 0.975). Ultra’s positive predictive value and negative predictive value were 79.8% and 57.1% respectively.
Conclusions
Tissue specimens from interventional bronchoscopy combined with Ultra provide a sensitive method for diagnosing smear-negative pulmonary tuberculosis, but its specificity was lower than Xpert.
Journal Article
Saliency-Based Rotor Spatial Position Displacement Self-Sensing for Self-Bearing Machines
Self-bearing machines do not contain physical bearings but magnetic bearings. Both rotor rotary and spatial positions displacement are required in these types of machines to control the rotor position while it is levitating. Self-bearing machines often use external sensors for x (horizontal) and y (vertical) spatial position measurement, which will result in additional cost, volume, complexity, and number of parts susceptible to failure. To overcome these issues, this paper proposes a xy-position estimation self-sensing technique based on both main- and cross-inductance variation. The proposed method estimates x and y position based on inductive saliency between two sets of three-phase coils. The proposed idea is applied on a combined winding self-bearing machine which does not require additional suspension force winding. No additional search coil placement for xy-position estimation is required. Therefore, the proposed algorithm can result in a compact size self-bearing machine that does not require external sensors for xy-position measurement and suspension force winding.
Journal Article
Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells
Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and
Xbp1s
transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.
The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4+ T cells and that methionine supplementation promotes CD4+ T cell dependent anti-tumor immune responses.
Journal Article
A Novel Beam Tracking Method for Silicon-Based Optical Phased Array Under Inter-Satellite Vibrations
To meet the miniaturization and lightweight requirements of inter-satellite laser communication, this study investigates the servo control system of a silicon-based optical phased array (OPA). Based on the far-field radiation model for beam steering of the silicon-based OPA, combined with thermo-optic phase modulation technology and time domain response, the transfer function of the silicon-based OPA is established. To address noise and disturbances encountered during actual tracking, a silicon-based OPA beam tracking method for satellite platform vibration is proposed. The control algorithm employs a Kalman filter-based Model Predictive Control (KF-MPC) strategy. The advantages of the designed control algorithm were verified through simulations and experiments. Step response simulation results show that compared with the traditional PID control algorithm, the proposed algorithm reduces overshoot by 15.1% and shortens the response time by 76.4%. Sinusoidal tracking simulation results indicate a 27.15% improvement in tracking accuracy over the traditional PID algorithm. Experimental results demonstrate that the tracking accuracy of the servo control system with the proposed algorithm is 155.45 μrad, while that using the PID algorithm is 210.97 μrad, representing a 26.31% improvement in tracking accuracy. This research provides a valuable reference for the application of silicon-based OPA in inter-satellite laser communication.
Journal Article
AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway
Background
AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined.
Methods
AMPKα1
fl/fl
Foxp3
YFP-Cre
,
Foxp3
YFP-Cre
,
Rag1
−/−
, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation.
Results
The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3β (GSK-3β), inhibiting the expression of PD-1 in Tregs.
Conclusion
Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3β signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.
Journal Article
Complex interplay between type 2 diabetes mellitus and pancreatic cancer: insights from observational and mendelian randomization analyses
Background
To investigate the causal relationship between type 2 diabetes mellitus (T2DM), pancreatic cancer (PC) risk and identify the mediating effects of various risk factors on that relationship.
Methods
581 PC patients and 582 healthy controls who visited our center from January 2013 to December 2023 were included in this retrospective study. Multivariable logistic regression was performed to evaluate the association between T2DM and PC through odds ratios (ORs) and 95% confidence intervals (CIs). Mendelian randomization (MR) studies were then conducted to explore the causal relationship between T2DM and PC, and causal mediation analysis (CMA) to examine the mediating role of common risk factors.
Results
After adjusting for confounding factors, retrospective analysis revealed significant association between new-onset diabetes mellitus (NODM) and PC risk, with insulin treatment also linked to increased PC development. The standard inverse-variance weighted (IVW) method indicated that genetic susceptibility to T2DM was associated with an increased risk of developing PC (OR = 1.11; 95% CI = 1.034–1.193). Furthermore, MR showed T2DM, insulin treatment, FGF-4, and sulfhydryl oxidase 2 may be independently associated with the prevalence of PC. Specially, CMA demonstrated that insulin treatment, FGF4, and sulfhydryl oxidase 2 mediate the pathway from T2DM to PC, contributing 56.8%, 55.8%, and 5.9% of the total effect, respectively.
Conclusion
This study supports the association between T2DM, specifically NODM, and increased PC risk, with insulin therapy, FGF4, and sulfhydryl oxidase 2 mediating this pathway. Further research is required to elucidate the mechanisms underlying these mediating effects.
Clinical trial number
not applicable.
Journal Article
Active bridging hydride species in ZnO nanorods originated from hydroxyl and oxygen vacancy
The bridging hydride species (Zn-H-Zn) formed via H
2
dissociation on ZnO surface play crucial roles in hydrogenation of unsaturated hydrocarbon to industrial production. Here, we find that the migration of surface hydroxyl in ZnO nanorods to nearby oxygen vacancy can also lead to the formation of this Zn-H-Zn species that are reactive to CO
2
hydrogenation to methanol using solid-state NMR spectroscopy. Below 100 °C, bridging Zn-H-Zn species show no activity toward CO
2
activation, while formate species are formed via the reaction of CO
2
with surface hydroxyl groups. At 150-200 °C, Zn-H-Zn species hydrogenate formate to methoxy species. At 250 °C, methanol is produced and desorbs from the ZnO surface. These results confirm the methanol formation mechanism via formate and methoxy intermediates in the presence of active bridging Zn-H-Zn species. This work reveals a new source of active hydrogen species in ZnO nanorods without introducing H
2
, which is highly significant for heterogeneous hydrogenation reactions.
The bridging hydride species (Zn–H–Zn), commonly formed through H₂ dissociation on ZnO surfaces, are essential for hydrogenating unsaturated hydrocarbons. Here, the authors show that surface hydroxyls on ZnO nanorods can migrate to nearby oxygen vacancies and similarly generate reactive Zn–H–Zn species, which they identify by solid-state NMR spectroscopy as active in CO₂ hydrogenation to methanol.
Journal Article