Harnessing Mechanical Stress with Viscoelastic Biomaterials for Periodontal Ligament Regeneration.

The viscoelasticity of mechanically sensitive tissues such as periodontal ligaments (PDLs) is key in maintaining mechanical homeostasis. Unfortunately, PDLs easily lose viscoelasticity (e.g., stress relaxation) during periodontitis or dental trauma, which disrupt cell-extracellular matrix (ECM) interactions and accelerates tissue damage. Here, Pluronic F127 diacrylate (F127DA) hydrogels with PDL-matched stress relaxation rates and high elastic moduli are developed. The hydrogel viscoelasticity is modulated without chemical cross-linking by controlling precursor concentrations. Under cytomechanical loading, F127DA hydrogels with fast relaxation rates significantly improved the fibrogenic differentiation potential of PDL stem cells (PDLSCs), while cells cultured on F127DA hydrogels with various stress relaxation rates exhibited similar fibrogenic differentiation potentials with limited cell spreading and traction forces under static conditions. Mechanically, faster-relaxing F127DA hydrogels leveraged cytomechanical loading to activate PDLSC mechanotransduction by upregulating integrin-focal adhesion kinase pathway and thus cytoskeletal rearrangement, reinforcing cell-ECM interactions. In vivo experiments confirm that faster-relaxing F127DA hydrogels significantly promoted PDL repair and reduced abnormal healing (e.g., root resorption and ankyloses) in delayed replantation of avulsed teeth. This study firstly investigated how matrix nonlinear viscoelasticity influences the fibrogenesis of PDLSCs under mechanical stimuli, and it reveals the underlying mechanobiology, which suggests novel strategies for PDL regeneration.

Non-Impacted Third Molars: Angels or Devils?

Third molars, also known as wisdom teeth, are located in the most posterior of the tooth arch [...].

NADPH-dependent ROS accumulation contributes to the impaired osteogenic differentiation of periodontal ligament stem cells under high glucose conditions.

Diabetes mellitus is an established risk factor for periodontal disease that can aggravate the severity of periodontal inflammation and accelerate periodontal destruction. The chronic high glucose condition is a hallmark of diabetes-related pathogenesis, and has been demonstrated to impair the osteogenic differentiation of periodontal ligament stem cells (PDLSCs), leading to delayed recovery of periodontal defects in diabetic patients. Reactive oxygen species (ROS) are small molecules that can influence cell fate determination and the direction of cell differentiation. Although excessive accumulation of ROS has been found to be associated with high glucose-induced cell damage, the underlying mechanisms remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) is an important electron donor and functions as a critical ROS scavenger in antioxidant systems. It has been identified as a key mediator of various biological processes, including energy metabolism and cell differentiation. However, whether NADPH is involved in the dysregulation of ROS and further compromise of PDLSC osteogenic differentiation under high glucose conditions is still not known. In the present study, we found that PDLSCs incubated under high glucose conditions showed impaired osteogenic differentiation, excessive ROS accumulation and increased NADPH production. Furthermore, after inhibiting the synthesis of NADPH, the osteogenic differentiation of PDLSCs was significantly enhanced, accompanied by reduced cellular ROS accumulation. Our findings demonstrated the crucial role of NADPH in regulating cellular osteogenic differentiation under high glucose conditions and suggested a new target for rescuing high glucose-induced cell dysfunction and promoting tissue regeneration in the future.

Appropriate antibiotic therapy is a predictor of outcome in patients with Stenotrophomonas maltophilia blood stream infection in the intensive care unit.

BACKGROUND/PURPOSE: The study was to assess the relationship between antibiotic therapy and the outcome in intensive care unit (ICU) patients with Stenotrophomonas maltophilia bloodstream infection (BSI). METHODS: ICU patients with monomicrobial S. maltophilia BSI from January 2004 to December 2019 were included and divided into two groups-those with- and without appropriate antibiotic therapy after BSI-for comparison. The primary outcome was the relationship between appropriate antibiotic therapy and 14-day mortality. The secondary outcome was the influence of different antibiotic therapies: levofloxacin- and trimethoprim-sulfamethoxazole (TMP/SMX)-containing regimens, on 14-day mortality. RESULTS: A total of 214 ICU patients were included. Patients received appropriate antibiotic therapy (n = 133) after BSI had a lower 14-day mortality than those (n = 81) without appropriate antibiotic therapy (10.5% vs. 46.9%, p < 0.001). No difference on 14-day mortality between groups of patients by time of appropriate antibiotic therapy was observed (p > 0.05). After a propensity score matching, the results is consistent that 14-day mortality were lower in patients with appropriate antibiotic therapy than those without appropriate antibiotic therapy (11.5% vs. 39.3%, p < 0.001). Among patients with S. maltophilia BSI receiving appropriate antibiotic therapy, there was a trend levofloxacin-containing regimens is associated with lower mortality than TMP/SMX-containing regimens (HR 0.233, 95% CI 0.050-1.084, p = 0.063). CONCLUSION: Appropriate antibiotic therapy was associated with decreased 14-day mortality in ICU patients with S. maltophilia BSI regardless of time. Levofloxacin-containing regimens may be better choice than TMP/SMX -containing regimens in treating ICU patients with S. maltophilia BSI.

Long non-coding RNA AC018926.2 regulates palmitic acid exposure-compromised osteogenic potential of periodontal ligament stem cells via the ITGA2/FAK/AKT pathway.

Although obesity has been proposed as a risk factor for periodontitis, the influence of excessive fat accumulation on the development of periodontitis and periodontal recovery from disease remains largely unknown. This study investigated the cellular response of periodontal ligament stem cells (PDLSCs) to elevated levels of a specific fatty acid, namely, palmitic acid (PA). The mechanism by which PA exposure compromises the osteogenic potential of cells was also explored. It was found that exposure of PDLSCs to abundant PA led to decreased cell osteogenic differentiation. Given that long non-coding RNAs (lncRNAs) play a key role in the stem cell response to adverse environmental stimuli, we screened the lncRNAs that were differentially expressed in PDLSCs following PA exposure using lncRNA microarray analysis, and AC018926.2 was identified as the lncRNA that was most sensitive to PA. Next, gain/loss-of-function studies illustrated that AC018926.2 was an important regulator in PA-mediated osteogenic differentiation of PDLSCs. Mechanistically, AC018926.2 upregulated integrin α2 (ITGA2) expression and therefore activated ITGA2/FAK/AKT signalling. Further functional studies revealed that inactivation of ITGA2/FAK/AKT signalling by silencing ITGA2 counteracted the pro-osteogenic effect induced by AC018926.2 overexpression. Moreover, the results of bioinformatics analysis and RNA immunoprecipitation assay suggested that AC018926.2 might transcriptionally regulate ITGA2 expression by binding to PARP1 protein. Our data suggest that AC018926.2 may serve as a therapeutic target for the management of periodontitis in obese patients.

Enhancing the nonreciprocal Goos-Hänchen shift by the Fano resonance of coupled gyromagnetic chains at normal incidence.

We report a resonance-enhanced nonreciprocal Goos-Hänchen (GH) shift for the wave reflected from the coupled gyromagnetic chains. We demonstrate that the Fano resonance enhances the GH shift with high reflectivity at normal incidence, and the resonance results from the interference between the leaky guided modes of the coupled chains. Furthermore, we show that the GH shift can be controlled by the number of stacked chains. The Fano resonance-enhanced GH shift offers a new efficiently way to enhance and control the GH shift for reflected wave beam. Such coupled gyromagnetic chains provide an extremely compact way for the devices such as unidirectional couplers and other integration photonic components, paving the way for the applications of nonreciprocal GH shift.

Roles of extracellular vesicles in periodontal homeostasis and their therapeutic potential.

Periodontal tissue is a highly dynamic and frequently stimulated area where homeostasis is easily destroyed, leading to proinflammatory periodontal diseases. Bacteria-bacteria and cell-bacteria interactions play pivotal roles in periodontal homeostasis and disease progression. Several reviews have comprehensively summarized the roles of bacteria and stem cells in periodontal homeostasis. However, they did not describe the roles of extracellular vesicles (EVs) from bacteria and cells. As communication mediators evolutionarily conserved from bacteria to eukaryotic cells, EVs secreted by bacteria or cells can mediate interactions between bacteria and their hosts, thereby offering great promise for the maintenance of periodontal homeostasis. This review offers an overview of EV biogenesis, the effects of EVs on periodontal homeostasis, and recent advances in EV-based periodontal regenerative strategies. Specifically, we document the pathogenic roles of bacteria-derived EVs (BEVs) in periodontal dyshomeostasis, focusing on plaque biofilm formation, immune evasion, inflammatory pathway activation and tissue destruction. Moreover, we summarize recent advancements in cell-derived EVs (CEVs) in periodontal homeostasis, emphasizing the multifunctional biological effects of CEVs on periodontal tissue regeneration. Finally, we discuss future challenges and practical perspectives for the clinical translation of EV-based therapies for periodontitis.

Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice.

The repetitive applications of vaccine boosters have been brought up in face of continuous emergence of SARS-CoV-2 variants with neutralization escape mutations, but their protective efficacy and potential adverse effects remain largely unknown. Here, we compared the humoral and cellular immune responses of an extended course of recombinant receptor binding domain (RBD) vaccine boosters with those from conventional immunization strategy in a Balb/c mice model. Multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells. Mechanistically, we confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance. Our findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies.

Network pharmacology and experimental evidence reveal the protective mechanism of Yi-Qi Cong-Ming decoction on age-related hearing loss.

CONTEXT: Yi-Qi Cong-Ming (YQCM) decoction has been widely used to prevent age-related hearing loss (ARHL), the most prevalent neurodegenerative disease in the elderly. OBJECTIVE: To explore the mechanism of YQCM decoction in the treatment of ARHL. MATERIALS AND METHODS: The chemical constituents of YQCM were screened from the Traditional Chinese Medicine Systems Pharmacology Database. Potential targets of YQCM against ARHL were predicted by DrugBank, GeneCards, and OMIM database. Protein-protein network and enrichment analysis were used for exploring possible molecular mechanisms. Molecular docking and an in vitro model of ARHL by exposing auditory cells with 100 µM H2O2 for 3 h were applied. Cell viability and mitochondrial membrane potential (ΔΨM) were detected by CCK-8 and high-content analysis. γH2AX and cleaved caspase-3 were detected by Western blot. RESULTS: The main compounds have good affinities with hub targets, especially AKT1, PTGS2, and CASP3. GO and KEGG analysis showed that the main biological process and key targets were related to negative regulation of the apoptotic process. H2O2 treatment could reduce the cell viability by 68% and impaired ΔΨM, while 90 µg/mL YQCM pre-treatment could restore the cell viability by 97.45% and increase ΔΨM (2-fold higher). YQCM pre-treatment also reduced γH2AX and cleaved caspase-3 protein levels. CONCLUSIONS: Our study suggested that YQCM prevents ARHL by modulating the apoptosis process in auditory hair cells. Moreover, this study proved that bioinformatics analysis combined with molecular docking and cell model is a promising method to explore other possible pharmacological interventions of ARHL.

Gold nanoparticles targeting the autophagy-lysosome system to combat the inflammation-compromised osteogenic potential of periodontal ligament stem cells: From mechanism to therapy.

Although substantial data indicate that the osteogenic potential of periodontal ligament stem cells (PDLSCs) is compromised under inflammatory conditions, the underlying mechanism remains largely unexplored. In this study, we found that both the autophagy levels and autophagic flux levels were decreased in PDLSCs incubated under inflammatory conditions (I-PDLSCs). Based on the increased expression of LC3 II (at an autophagy level) and decreased accumulation of LC3 II (at an autophagic flux level) in I-PDLSCs, we speculated that the disruption of I-PDLSC autophagy arose from dysfunction of the cellular autophagy-lysosome system. Subsequently, our hypothesis was demonstrated by inhibited autophagosome-lysosome fusion, damaged lysosomal function, and suppressed activation of transcription factor EB (TFEB, a master regulator of the autophagy-lysosome system) in I-PDLSCs and verified by TFEB overexpression in I-PDLSCs. We found that gold nanoparticle (Au NP) treatment rescued the osteogenic potential of I-PDLSCs by restoring the inflammation-compromised autophagy-lysosome system. In this context, Au NP ceased to be effective when TFEB was knocked down in PDLSCs. Our data demonstrate the crucial role of the autophagy-lysosome system in cellular osteogenesis under inflammatory conditions and suggest a new target for rescuing inflammation-induced cell dysfunction using nanomaterials to aid cell biology and tissue regeneration.

Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway.

BACKGROUND: High glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) has long been a challenge to periodontal regeneration for diabetic individuals. Metformin is an anti-hyperglycemic drug that exhibits abundant biological activities associated with cell metabolism and downstream tissue regeneration. However, how metformin combats damage to PDLSC osteogenic differentiation under high glucose and the underlying mechanisms remain unknown. METHODS: Osteogenic differentiation of PDLSCs was assessed by alkaline phosphatase (ALP) staining, ALP activity, Alizarin Red staining and quantitative assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. RNA-seq analysis was performed to screen target genes of metformin, and the effects of target genes were confirmed using lentivirus transfection. Western blot analysis was also used to detect the protein level of underlying signaling pathways. RESULTS: We found that osteogenic differentiation of PDLSCs under high glucose was decreased, and metformin addition enhanced this capacity of differentiation. Furthermore, the results of RNA-seq analysis showed that natriuretic peptide receptor 3 (NPR3) was upregulated in PDLSCs under high glucose and downregulated after metformin addition. When the underlying pathways involved were investigated, we found that upregulation of NPR3 can compromise the metformin-enhanced PDLSC osteogenic differentiation and activate the MAPK pathway (especially the p38 MAPK and Erk1/2 pathway), and that inhibition of the NPR3-mediated p38 MAPK or Erk1/2 pathway enhanced the osteogenic differentiation of PDLSCs under high glucose. CONCLUSIONS: The present study suggests that metformin may enhance the osteogenic differentiation of PDLSCs under high glucose via downregulation of NPR3 and inhibition of its downstream MAPK pathway. This is the first report identifying the involvement of NPR3-mediated MAPK pathway in the metformin-enhanced osteogenic differentiation, indicating that NPR3 antagonists, such as metformin, may be feasible therapeutics for periodontal tissue regeneration in diabetic individuals.

Emergence of concurrent levofloxacin- and trimethoprim/sulfamethoxazole-resistant Stenotrophomonas maltophilia: Risk factors and antimicrobial sensitivity pattern analysis from a single medical center in Taiwan.

BACKGROUND: The emergence of concurrent levofloxacin- and trimethoprim/sulfamethoxazole (TMP/SMX)-resistant Stenotrophomonas maltophilia (LTSRSM) in Taiwan is becoming a serious problem, but clinical data analysis on this has not been reported. METHODS: A matched case-control-control study was conducted to investigate risk factors for LTSRSM occurrence in hospitalized patients. For patients with LTSRSM infection/colonization (the case group), two matched control groups were used: control group A with levofloxacin- and TMP/SMX-susceptible S. maltophilia (LTSSSM) and control group B without S. maltophilia. Besides, tigecycline, ceftazidime, cefepime, ciprofloxacin, gentamicin, amikacin, and colistin susceptibilities in collected LTSRSM and levofloxacin- and TMP/SMX-susceptible S. maltophilia (LTSSSM) isolates were compared. RESULTS: From January 2014 to June 2016, 129 LTSRSM from cultured 1213 S. maltophilia isolates (10.6%) were identified. A total of 107 LTSRSM infected patients paired with 107 LTSSSM-, and 107 non-S. maltophilia-infected ones were included. When compared with control group A, previous fluoroquinolone and TMP/SMX use was found to be independently associated with LTSRSM occurrence. When compared with control group B, mechanical ventilation, cerebrovascular disease, and previous fluoroquinolone use were risk factors for LTSRSM occurrence. Eighty-five LTSRSM and 85 LTSSSM isolates were compared for antibiotic susceptibilities; the resistance rates and minimum inhibitory concentrations of tigecycline and ceftazidime were significantly higher for LTSRSM than for LTSSSM isolates. CONCLUSION: The emergence of LTSRSM showing cross resistance to tigecycline and ceftazidime would further limit current therapeutic options. Cautious fluoroquinolone and TMP/SMX use may be helpful to limit such high-level resistant strains of S. maltophilia occurrence.

Broadband radar cross section reduction by an absorptive metasurface based on a magnetic absorbing material.

A highly feasible approach to achieve a broadband radar cross section (RCS) reduction using a simple magnetic metasurface is presented. A magnetic absorbing material (MAM) with high permittivity and magnetic loss is introduced into the metasurface design instead of the more common dielectric material to considerably reduce its thickness. The metasurface is composed of an optimized two-dimensional array of MAM meta-atoms and a metal plate in back. The meta-atoms share a simple square ring shape but with variable geometrical parameters, forming strong absorption in different frequency bands with large reflection phase differences. By hybridizing the absorption and phase-cancelation technique, a 10-dB RCS reduction from 3.4 to 18 GHz is achieved at a thickness of only 4 mm. Further experimental measurements are provided to evaluate the performance. Our work provides a promising way to broaden the bandwidth of RCS reduction with low density, reduced thickness, and stable performance, which can be utilized in harsh physical and chemical environments.

Broadband trifunctional metasurface and its application in a lens antenna.

Multifunctional metasurfaces have attracted extensive attention due to their ability to achieve diversified wavefront controls in flat devices. To date, most designs through metasurface are confined to realize one or two functionalities. In this work, we implement a broadband trifunctional metasurface by using different meta-atoms of the same type. The meta-atoms can independently manipulate the amplitude and phase of transmitted waves and the phase of reflected waves in a wide frequency range. Thus, they help the metasurface achieving the functionalities of beam deflection, diffuse scattering, and beam focusing according to the polarization and the direction of incident waves. The metasurface is applied to a metalens antenna, which features broadband, low side-lobe, and stealth. The metalens antenna works at the frequency range 9.8 GHz to 11.6 GHz with gain over 25 dBi. Experiments verify the functions of the trifunctional metasurface and are in good agreement with the designs. Our approach provides a solid platform for high-efficiency wideband metadevices with diverse functionalities.

Invisible Gateway by Superscattering Effect of Metamaterials.

Illusion devices, such as superscatterer and invisible gateway, have been theoretically studied under the theory of transformation optics and folded geometry transformations. The realization of these devices needs building blocks of metamaterials with negative permittivities and permeabilities. However, superscattering effects, such as stopping wave propagation in an air channel, have not been verified from illusion devices physically because of the challenge of metamaterial design, fabrication, and material loss. In this Letter, we implement a big metamaterial superscatterer, and experimentally demonstrate its superscattering effect at microwave frequencies by field-mapping technology. We confirm that superscattering is originated from the excitation of surface plasmons. Integrated with superscatterer, we experimentally display that an invisible gateway could stop electromagnetic waves in an air channel with a width much larger than the cutoff width of the corresponding rectangular waveguide. Our results provide a first direct observation of superscattering effect of double negative metamaterials and invisible gateway for electromagnetic waves. It builds up an ideal platform for future designs of other illusion devices.

Periodontitis-compromised dental pulp stem cells secrete extracellular vesicles carrying miRNA-378a promote local angiogenesis by targeting Sufu to activate the Hedgehog/Gli1 signalling.

OBJECTIVES: Previously, our investigations demonstrated robust pro-angiogenic potentials of extracellular vesicles secreted by periodontitis-compromised dental pulp stem cells (P-EVs) when compared to those from healthy DPSCs (H-EVs), but the underlying mechanism remains unknown. MATERIALS AND METHODS: Here, circulating microRNAs (miRNAs) specifically found in P-EVs (compared with H-EVs) were identified by Agilent miRNA microarray analysis, and the roles of the candidate miRNA in P-EV-enhanced cell angiogenesis were confirmed by cell transfection and RNA interference methods. Next, the direct binding affinity between the candidate miRNA and its target gene was evaluated by luciferase reporter assay. CCK-8, transwell/scratch wound healing and tube formation assays were established to investigate the proliferation, migration, and tube formation abilities of endothelial cells (ECs). Western blot was employed to measure the protein levels of Hedgehog/Gli1 signalling pathway components and angiogenesis-related factors. RESULTS: The angiogenesis-related miRNA miR-378a was found to be enriched in P-EVs, and its role in P-EV-enhanced cell angiogenesis was confirmed, wherein Sufu was identified as a downstream target gene of miR-378a. Functionally, silencing of Sufu stimulated EC proliferation, migration and tube formation by activating Hedgehog/Gli1 signalling. Further, we found that incubation with P-EVs enabled the transmission of P-EV-contained miR-378a to ECs. Subsequently, the expressions of Sufu, Gli1 and vascular endothelial growth factor in ECs were significantly influenced by P-EV-mediated miR-378a transmission. CONCLUSIONS: These data suggest that P-EVs carrying miR-378a promote EC angiogenesis by downregulating Sufu to activate the Hedgehog/Gli1 signalling pathway. Our findings reveal a crucial role for EV-derived miR-378a in cell angiogenesis and hence offer a new target for modifying stem cells and their secreted EVs to enhance vessel regenerative potential.

An unusual case of reactivated latent pulmonary cryptococcal infection in a patient after short-term steroid and azathioprine therapy: a case report.

BACKGROUND: Cryptococcus is one of the major fungal pathogens infecting the lungs. Pulmonary cryptococcal infection is generally considered a community-acquired condition caused by inhalation of dust contaminated with fungal cells from the environment. Here, we report a case developing pulmonary cryptococcosis 3 months after hospital admission, which has rarely been reported before. CASE PRESENTATION: A 73-year-old female patient who was previously immunocompetent experienced persistent dry cough for 2 weeks, 3 months after admission. Chest computed tomography (CT) showed a new solitary pulmonary nodule developed in the upper lobe of the left lung. Staining and culture of expectorated sputum smears were negative for bacteria, acid-fast bacilli, or fungus. The patient then underwent biopsy of the lesion. Histopathology findings and a positive serum cryptococcal antigen titer (1:8) indicated pulmonary cryptococcosis. Daily intravenous 400 mg fluconazole was administered initially followed by oral fluconazole therapy. Follow-up chest CT after 3 months of antifungal therapy showed complete disappearance of the pulmonary nodule. Respiratory symptoms of the patient also resolved. A complete investigation excluded the possibility of a patient-to-patient transmission or primarily acquiring the infection from the hospital environment. Based on the patient's history of exposure to pigeons before admission and recent steroid and azathioprine use after admission for the treatment of myasthenic crisis, reactivation of a latent pulmonary cryptococcal infection acquired before admission, in this case, is impressed. CONCLUSIONS: Although rarely reported, pulmonary cryptococcal infection should be included in the differential diagnosis of hospitalized patients with respiratory symptoms, especially in those with predisposing risk factors. Chest image studies and further surgical biopsy are needed for confirmation.

Compact patch antenna enabled by a metasurface with stereo elements.

We implemented a novel compact antenna by applying a metasurface with stereo elements (stereo-MS) as the superstrate of a patch antenna. The stereo-MS, an array of stereo patches printed on a grooved dielectric substrate, enabled the footprint miniaturization and bandwidth enhancement of the patch antenna. The overall size reduction of the stereo-MS antenna is over 38% compared with the conventional plane metasurface (plane-MS) antenna working in the same frequency range. A prototype antenna working at 5.3 GHz was designed, fabricated, and measured. Experiments demonstrated the fractional impedance bandwidth of the antenna was 44.5% at criteria |S11 |< -10 dB, covering the frequencies 4.18 to 6.56 GHz, and the average gain about 6.9 dBi in the band. Experimental results were found in very good agreement with the design, which confirms the functionality of stereo-MS in antenna minimization. Our antenna features a compact size (0.409 λ02) and low profile (3.024 mm). The stereo-MSs provide a new way for the size miniaturization of microwave and optical devices, such as antennas.