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Yanyi Wang,1,2,* Juan Wen,1– 3,* Tong Lu,1,2 Wei Han,2,4 Kai Jiao,5 Huang Li1,2 1Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 2Medical School of Nanjing University, Nanjing, People’s Republic of China; 3Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), School of Dentistry, The University of Queensland, Brisbane, Queensland, 4006, Australia; 4Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 5Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Han, Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, 30 Central Road, Nanjing, 210008, People’s Republic of China, Email doctorhanwei@hotmail.com Huang Li, Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, 30 Central Road, Nanjing, 210008, People’s Republic of China, Tel +86-25-83620173, Fax +86-25-83620200, Email lihuang76@nju.edu.cnAbstract: Extracellular vesicles (EVs) can deliver various bioactive molecules among cells, making them promising diagnostic and therapeutic alternatives in diseases. Mesenchymal stem cell-derived EVs (MSC-EVs) have shown therapeutic potential similar to MSCs but with drawbacks such as lower yield, reduced biological activities, off-target effects, and shorter half-lives. Improving strategies utilizing biotechniques to pretreat MSCs and enhance the properties of released EVs, as well as modifying MSC-EVs to enhance targeting abilities and achieve controlled release, shows potential for overcoming application limitations and enhancing therapeutic effects in treating bone-related diseases. This review focuses on recent advances in functionalizing MSC-EVs to treat bone-related diseases. Firstly, we underscore the significance of MSC-EVs in facilitating crosstalk between cells within the skeletal environment. Secondly, we highlight strategies of functional-modified EVs for treating bone-related diseases. We explore the pretreatment of stem cells using various biotechniques to enhance the properties of resulting EVs, as well as diverse approaches to modify MSC-EVs for targeted delivery and controlled release. Finally, we address the challenges and opportunities for further research on MSC-EVs in bone-related diseases.Keywords: extracellular vesicles, mesenchymal stem cells, functional modification, bone-related diseases

Ru Ma,1– 3 Hongling Su,1– 3 Keping Jiao,1– 3 Jian Liu1,2 1The First Clinical Medical College of Lanzhou University, Lanzhou City, Gansu Province, People’s Republic of China; 2Lanzhou University, Lanzhou City, Gansu Province, People’s Republic of China; 3Gansu Provincial People’s Hospital, Lanzhou, Gansu Province, People’s Republic of ChinaCorrespondence: Jian Liu, Department of Clinical Medicine, the First Clinical Medical College of Lanzhou University, No. 1, Donggang West Road, Chengguan District, Lanzhou City, Gansu Province, People’s Republic of China, Tel +86 136 0935 4197, Email medecinliu@sina.comBackground: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by neutrophils airway infiltration. It is currently known that Interleukin-17 (IL-17) is an important pro-inflammatory factor. It can promote the accumulation of neutrophils and participate in the chronic inflammatory process of COPD. However, the value of IL-17 levels in the diagnosis and assessment of COPD remains controversial. In view of this, we conducted a systematic review and meta-analysis to assess its relevance.Methods: We searched databases such as PubMed, Web of Science, Cochrane Library and Embase to extract original research.Results: A total of 10 studies with 2268 participants were included in this meta-analysis. The results showed that the level of serum IL-17 in patients with stable COPD was significantly higher than that in healthy controls (standard mean difference SMD, 1.59, 95% CI 0.84– 2.34; p< 0.001). Compared with the stable COPD group, the serum IL-17 level in acute exacerbation (AECOPD) was significantly higher (SMD, 1.78, 95% CI 1.22– 2.33; p< 0.001). The level of IL-17 in sputum of COPD patients was also higher than that of healthy controls (SMD, 2.03, 95% CI 0.74– 3.31; p< 0.001).Conclusion: Our results showed that IL-17 levels were elevated in serum and sputum in COPD patients compared with healthy controls, and IL-17 levels increased with disease progression. IL-17 serves as a potential biomarker to indicate the persistence of neutrophilic inflammation and exacerbation of COPD.Keywords: chronic obstructive pulmonary disease, Interleukin-17, proinflammatory factor, meta-analysis

In this study, a new cooling strategy for a proton exchange membrane (PEM) fuel cell stack is investigated using a three-dimensional (3D) multiphase non-isothermal model. The new cooling strategy follows that of the Honda's Clarity design and further extends to a cooling unit every five cells in stacks. The stack consists of 5 fuel cells sharing the inlet and outlet manifolds for reactant gas flows. Each cell has 7-path serpentine flow fields with a counter-flow configuration arranged for hydrogen and air streams. The coolant flow fields are set at the two sides of the stack and are simplified as the convective heat transfer thermal boundary conditions. This study also compares two thermal boundary conditions, namely limited and infinite coolant flow rates, and their impacts on the distributions of oxygen, liquid water, current density and membrane hydration. The difference of local temperature between these two cooling conditions is as much as 6.9 K in the 5-cell stack, while it is only 1.7 K in a single cell. In addition, the increased vapor concentration at high temperature (and hence water saturation pressure) dilutes the oxygen content in the air flow, reducing local oxygen concentration. The higher temperature in the stack also causes low membrane hydration, and consequently poor cell performance and non-uniform current density distribution, as disclosed by the simulation. The work indicates the new cooling strategy can be optimized by increasing the heat transfer coefficient between the stack and coolant to mitigate local overheating and cell performance reduction.

Liquid water transport in perforated gas diffusion layers (GDLs)is numerically investigated using a three-dimensional (3D)two-phase volume of fluid (VOF)model and a stochastic reconstruction model of GDL microstructures. Different perforation depths and diameters are investigated, in comparison with the GDL without perforation. It is found that perforation can considerably reduce the liquid water level inside a GDL. The perforation diameter (D = 100 μm)and the depth (H = 100 μm)show pronounced effect. In addition, two different perforation locations, i.e. the GDL center and the liquid water break-through point, are investigated. Results show that the latter perforation location works more efficiently. Moreover, the perforation perimeter wettability is studied, and it is found that a hydrophilic region around the perforation further reduces the water saturation. Finally, the oxygen transport in the partially-saturated GDL is studied using an oxygen diffusion model. Results indicate that perforation reduces the oxygen diffusion resistance in GDLs and improves the oxygen concentration at the GDL bottom up to 101% (D = 100 μm and H = 100 μm).

Contemporary models of intrafibrillar mineralization mechanisms are established using collagen fibrils as templates without considering the contribution from collagen-bound apatite nucleation inhibitors. However, collagen matrices destined for mineralization in vertebrates contain bound matrix proteins for intrafibrillar mineralization. Negatively charged, high-molecular weight polycarboxylic acid is cross-linked to reconstituted collagen to create a model for examining the contribution of collagen-ligand interaction to intrafibrillar mineralization. Cryogenic electron microscopy and molecular dynamics simulation show that, after cross-linking to collagen, the bound polyelectrolyte caches prenucleation cluster singlets into chain-like aggregates along the fibrillar surface to increase the pool of mineralization precursors available for intrafibrillar mineralization. Higher-quality mineralized scaffolds with better biomechanical properties are achieved compared with mineralization of unmodified scaffolds in polyelectrolyte-stabilized mineralization solution. Collagen-ligand interaction provides insights on the genesis of heterogeneously mineralized tissues and the potential causes of ectopic calcification in nonmineralized body tissues.

The cross flow in the under-land gas diffusion layer (GDL) between 2 adjacent channels plays an important role on water transport in proton exchange membrane fuel cell. A 3-dimensional (3D) two-phase model that is based on volume of fluid is developed to study the liquid water-air cross flow within the GDL between 2 adjacent channels. By considering the detailed GDL microstructures, various types of air-water cross flows are investigated by 3D numerical simulation. Liquid water at 4 locations is studied, including droplets at the GDL surface and liquid at the GDL-catalyst layer interface. It is found that the water droplet at the higher-pressure channel corner is easier to be removed by cross flow compared with droplets at other locations. Large pressure difference Δp facilitates the faster water removal from the higher-pressure channel. The contact angle of the GDL fiber is the key parameter that determines the cross flow of the droplet in the higher-pressure channel. It is observed that the droplet in the higher-pressure channel is difficult to flow through the hydrophobic GDL. Numerical simulations are also performed to investigate the water emerging process from different pores of the GDL bottom. It is found that the amount of liquid water removed by cross flow mainly depends on the pore's location, and the water under the land is removed entirely into the lower-pressure channel by cross flow.

This paper proposes a three-dimensional (3D) volume of fluid (VOF) study to investigate two-phase flow in the gas diffusion layer (GDL) of proton exchange membrane (PEM) fuel cells and liquid water distribution. A stochastic model was adopted to reconstruct the 3D microstructures of Toray carbon papers and incorporate the experimentally-determined varying porosity. The VOF predictions were compared with the water profiles obtained by the X-ray tomographic microscopy (XTM) and the Leverett correlation. It was found local water profiles are similar in the sample’s sub-regions under the pressure difference p = 1000 Pa between the two GDL surfaces, but may vary significantly under p = 6000 Pa. The water-air interfaces inside the GDL structure were presented to show water distribution and breakthrough.

In this study, the effective oxygen diffusivity in the dry or partially-saturated gas diffusion layer (GDL) is numerically investigated by an oxygen diffusion model in GDLs reconstructed by a stochastic method. The predicted effective diffusivity in dry GDLs is compared with various diffusivity models from literatures. Reasonable agreements with other models were obtained. The effect of the PTFE loading in the dry Toray carbon paper is also investigated and compared with recent experimental data. It is found that the effective diffusivity becomes lower under higher PTFE loading due to the decreased pore volume, as expected. The relative effective oxygen diffusivity in partially-saturated GDLs is calculated using the two-phase volume of fluid (VOF) model and an oxygen diffusion model. The effects of different local water profiles and porosity distribution on the effective oxygen diffusivity in both the through-plane (TP) and in-plane (IP) directions are investigated and compared with a lattice Boltzmann model and experimental data. The present results are in good agreement with other studies. It is found that local water profile has significant impacts on the effective diffusivity in partially-saturated GDLs and the diffusivity in the TP direction is more sensitive to the water distribution than the IP direction.

Pompe disease (OMIM 232300) is a rare autosomal recessive metabolic disorder characteristic by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA) due to pathogenic variations in the GAA gene. Over 560 variants have been identified, leading to a wide phenotypic spectrum ranging from classic infantile to late-onset Pompe disease (LOPD). We performed a comprehensive analysis of a Chinese family with LOPD). Family members were assessed through clinical history, laboratory data, muscle pathology, and whole-exome sequencing. In vitro functional studies were performed to characterize the novel variant. We identified a novel GAA variant c.568C>G, p.(R190G) in trans with the known pathogenic variant c.1082C>T, p.(P361L). The proband exhibited a mild limb-girdle phenotype, with notable proximal weakness and a 20-year history of abnormal gait, without early respiratory involvement. Biochemical analysis showed a profound reduction in GAA enzymatic activity. In vitro studies confirmed a significant decrease in the stability and function of the GAA-R190G variant. Overexpression of this variant in HEK293 cells yielded a 5% residual activity of GAA as compared to wild type (WT) GAA. In addition, by Western blotting the 110 kD band of the precursor of GAA was not detectable in medium and the 76 kD band of functional GAA was drastically reduced in cell lysates. The identification of the novel pathogenic GAA variant c.568C>G, p.(R190G) expands the mutational spectrum of the GAA gene. Symptom variability in LOPD underscores the need for high-risk screening for specific populations. [ABSTRACT FROM AUTHOR]

Late-onset Pompe disease (LOPD) typically presents with insidious onset and non-specific early symptoms, leading to frequent diagnostic delays. The spectrum of genetic mutations in Chinese LOPD patients differs from that seen in the rest of the world, and previous research suggests difference in high-risk screening profiles. However, the clinical picture of adolescent LOPD is underrepresented. Thus, this study aimed to expand the cohort for high-risk screening and investigate the correlation between acid alpha-glucosidase (GAA) gene mutations and clinical phenotypes. Inclusion criteria were amended according to previous studies: (1) patients aged ≥1 year; (2) undiagnosed myopathy patients with at least one of the following: (a) serum creatine kinase (CK) levels exceeding 1.5 times the upper limit of normal (ULN) at least twice within a month, (b) weakness in axial and/or proximal limb muscles, or (c) unexplained respiratory distress. From April 2021 to April 2022, 31 medical centers across China assessed GAA activity using dried blood spots (DBS) and tandem mass spectrometry (MS/MS). Patients with GAA activity below lower normal limit underwent next-generation sequencing (NGS) of the GAA gene, and the clinical-genetic correlations of diagnosed patients were analyzed. A total of 726 individuals were screened, with 44 (6.1%) exhibiting reduced GAA activity among whom 16 (2.2%) were diagnosed with LOPD. At the time of diagnosis, most patients (13/16) exhibited varying degrees of respiratory system involvement, and all confirmed cases showed significant weakness in axial and proximal limb muscles. Among patients with onset ≤16 years (4/16), CK levels averaged 5.9±2.2 times ULN, with a c.2238G>C mutation frequency of 12.5% (1/8). For those with onset >16 years (12/16), CK levels were at 1.9±1.0 times ULN, with a c.2238G>C mutation frequency of 45.8% (11/24). Additionally, three previously unreported GAA mutations were identified: c.521A>G (p.E174G), c.839_840insCC (p.R281fs), and c.1444 C>T (p.P482S). Overall, Chinese patients with LOPD exhibit more pronounced respiratory involvement and less frequent hyperCKemia. Patients with onset before age 16 show higher CK levels but a lower frequency of the c.2238G>C mutation. Different early high-risk screening standards should be established for children/adolescents and adults with LOPD. [ABSTRACT FROM AUTHOR]

GNE myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. In China, as the most populous country in the world, it is crucial to comprehend the genetic and clinical characteristics of GNE myopathy for effective diagnosis, management, and therapeutic interventions. This multi-center study aimed to delineate the clinical phenotype and GNE mutation spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations. We retrospectively analyzed GNE variants from 113 patients, integrating this data with external GNE variants from online databases for a global perspective on GNE mutations, examining their consequences, distribution, ethnicity, and severity. Our mutation analysis revealed 101 distinct GNE mutations, with 38.6% being previously unreported. Sanger sequencing revealed two patients (P48, P58) with deep intronic variant (DIV) c.862+870C>T, while whole genome sequencing (WGS) uncovered three more mutations: c.52-8924G>T, c.1505-12G>A, and c.1445_1447dup, respectively. Predominantly, missense mutations, particularly the c.620A>T variant, were observed, highlighting it as a key pathogenic variant in the Chinese population. Comparative studies with Japanese, Korean, and Jewish cohorts showed later onset ages in Chinese patients, suggesting a milder phenotype influenced by ethnic and geographical factors. The study emphasizes the importance of comprehensive genetic screening, including advanced techniques like WGS and Nanopore long reads sequencing to capture the full spectrum of GNE mutations. Remarkably, patients with the p.D207V mutation had a significantly delayed progression to wheelchair dependence and ambulation loss. Given the common mutation p.D207V, GNE myopathy's milder phenotype might lead to underdiagnosis in China. [ABSTRACT FROM AUTHOR]