Local E-rhBMP-2/ß-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model.

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/ß-Tricalcium phosphate (E-rhBMP-2/ß-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/ß-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/ß-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/ß-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.

Bulk RNA-seq analyses of mandibular condylar cartilage in a post-traumatic TMJ osteoarthritis rabbit model.

OBJECTIVE: The temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome-wide profiling to identify new signalling pathways critical for cellular functions during OA pathology. MATERIALS AND METHODS: Temporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA-seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. RESULTS/CONCLUSIONS: Our study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K-Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA.

Macrocycle-Surfaced Polymer Nanocapsules: An Emerging Paradigm for Biomedical Applications.

In the recent decade, macrocycle-surfaced polymer nanocapsules have been developed and studied as potential drug carriers. In particular, a unique group of these nanocapsules were constructed from a covalently self-assembled polymer network based on several classic macrocycles including cucurbituril, pillararene, and calixarene. The unique structure of these nanocapsules consists of a liquid or solid core and a shell laced with macrocycles in which the macrocycles not only act as the shell matrix of the nanocapsules but also allow further facile, modular functionalization via host-guest interactions with guest-tagged molecules. More interestingly, when a responsive cross-linker was introduced between the macrocycles, the payload inside the nanocapsules could be selectively released in the presence of typical hallmarks of certain diseases, which is of great interest for biomedical applications. In this Topical Review, macrocycle-surfaced polymer nanocapsules derived from covalently self-assembled polymer networks are introduced systemically with a focus on the molecular design and biomedical applications.

Cucurbituril-Based Supramolecular Polymers for Biomedical Applications.

Supramolecular polymers (SPs) have attracted broad interest because of their intriguing features and functions. Host-guest interactions often impart tunable physicochemical properties, reversible hierarchical organization, and stimuli-responsiveness to SPs for diverse biomedical applications. Characterized by strong but dynamic interactions with guest molecules, cucurbit[n]uril (CB[n]) has shown great potential as an important building block of various functional polymers for biomedical applications. In this Minireview, we summarize the most recent examples regarding the design, fabrication, and biomedical applications of CB[n]-based supramolecular polymers (CSPs), which are categorized as noncovalent and covalent CSPs according to the interactions between the CB[n] and polymer backbones. The design principles of CSPs and their unique advantages for biomedical applications, as well as the developmental trends and future perspectives of this cross-disciplinary area are also discussed.

Supramolecular Induction of Mitochondrial Aggregation and Fusion.

Mitochondrial fission is often associated with the development of oxidative stress related diseases, as the fragmentation of mitochondria undermines their membranes, advances production of reactive oxygen species, and promotes apoptosis. Therefore, induction of mitochondrial aggregation and fusion could potentially reverse such medical conditions. Herein, a supramolecular strategy to induce mitochondrial aggregation and fusion is developed for the first time. A polyethylene glycol (PEG) system that was dually tagged with triphenylphosphonium (TPP) and adamantane (ADA), namely TPP-PEG-ADA, was designed to target mitochondria and functionalize their surfaces with ADA. Thereafter, the addition of cucurbit[7]uril (CB[7]) grafted hyaluronic acid (HA) induced supramolecular aggregation and fusion of mitochondria, via strong host-guest interactions between the CB[7] moiety of CB[7]-HA and ADA residing on the surface of mitochondria. As a proof-of-principle, chemically stressed SH-SY5Y cells and zebrafish neurons were effectively protected via this supramolecular mitochondrial fusion strategy in vitro and in vivo, respectively. This study may open up new venues in not only fundamentally controlling mitochondrial dynamics but also addressing the medical needs to treat diseases associated with mitochondrial fission and fragmentation.

Role of intracellular Ca2+-based mechanotransduction of human periodontal ligament fibroblasts.

Human periodontal ligament (hPDL) fibroblasts are thought to receive mechanical stress (MS) produced by orthodontic tooth movement, thereby regulating alveolar bone remodeling. However, the role of intracellular calcium ([Ca2+]i)-based mechanotransduction is not fully understood. We explored the MS-induced [Ca2+]i responses both in isolated hPDL fibroblasts and in intact hPDL tissue and investigated its possible role in alveolar bone remodeling. hPDL fibroblasts were obtained from healthy donors' premolars that had been extracted for orthodontic reasons. The oscillatory [Ca2+]i activity induced by static compressive force was measured by a live-cell Ca2+ imaging system and evaluated by several feature extraction method. The spatial pattern of cell-cell communication was investigated by Moran's I, an index of spatial autocorrelation and the gap junction (GJ) inhibitor. The Ca2+-transporting ionophore A23187 was used to further investigate the role of [Ca2+]i up-regulation in hPDL cell behavior. hPDL fibroblasts displayed autonomous [Ca2+]i responses. Compressive MS activated this autonomous responsive behavior with an increased percentage of responsive cells both in vitro and ex vivo. The integration, variance, maximum amplitude, waveform length, and index J in the [Ca2+]i responses were also significantly increased, whereas the mean power frequency was attenuated in response to MS. The increased Moran's I after MS indicated that MS might affect the pattern of cell-cell communication via GJs. Similar to the findings of MS-mediated regulation, the A23187-mediated [Ca2+]i uptake resulted in the up-regulation of receptor activator of NF-κB ligand (Rankl) and Sost along with increased sclerostin immunoreactivity, suggesting that [Ca2+]i signaling networks may be involved in bone remodeling. In addition, A23187-treated hPDL fibroblasts also showed the suppression of osteogenic differentiation and mineralization. Our findings suggest that augmented MS-mediated [Ca2+]i oscillations in hPDL fibroblasts enhance the production and release of bone regulatory signals via Rankl/Osteoprotegerin and the canonical Wnt/ß-catenin pathway as an early process in tooth movement-initiated alveolar bone remodeling.-Ei Hsu Hlaing, E., Ishihara, Y., Wang, Z., Odagaki, N., Kamioka, H. Role of intracellular Ca2+-based mechanotransduction of human periodontal ligament fibroblasts.

HBV DNA and HBsAg: Early Prediction of Response to Peginterferon α-2a in HBeAg-Negative Chronic Hepatitis B.

Objective: The proportion of hepatitis e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients in China has increased rapidly. However, the response of these patients to peginterferon (peg-IFN) treatment is poor, and the antiviral treatment strategies are inconsistent. This study aimed to investigate the role of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) in early prediction of response in HBeAg-negative CHB patients receiving peg-IFN α-2a. Patients and Methods: Treatment-naïve HBeAg-negative patients were involved in this prospective study during 2014-2018. The HBV DNA and HBsAg were quantified at baseline and during treatment (weeks 12, 24 and 48) in sera. The factors associated with HBV DNA undetectable and HBsAg <100 IU/ml at treatment 48 weeks were assessed. Results: This study involved 45 patients. There was HBV DNA undetectable in 36 cases (80%), including 19 (52.8%) with HBsAg <100 IU/ml at week 48. The HBV DNA <2.0 log10IU/ml at week 24 (PPV = 96.9%, NPV = 66.7%, P = 0.018) was an independent predictor of HBV DNA undetectable at week 48. The HBsAg <800 IU/ml at baseline (PPV = 92.1%, NPV = 69.7%, P = 0.054) and HBsAg decline >5.00-fold at week 24 (PPV = 83.3%, NPV = 77.8%, P = 0.038) were independent predictors of HBsAg <100 IU/ml and HBV DNA undetectable at week 48. Conclusion: Early on-treatment quantification of HBV DNA and HBsAg in patients with HBeAg-negative CHB treated with peg-IFN α-2a may help identify those likely to be cured by this method and optimize therapy strategies.

The expression and regulation of Wnt1 in tooth movement-initiated mechanotransduction.

INTRODUCTION: The Wnt signaling pathway acts as a key regulator of skeletal development and its homeostasis. However, the potential role of Wnt1 in the mechanotransduction machinery of orthodontic tooth movement-initiated bone remodeling is still unclear. Hence, this study focused on the regulatory dynamics of the Wnt1 expression in both the periodontal ligament (PDL) and osteocytes in vivo and in vitro. METHODS: The Wnt1 expression in the orthodontically moved maxillary first molar in mice was assessed at 0, 1, and 5 days, on both the compression and tension sides. Primary isolated human PDL (hPDL) fibroblasts, as well as murine long-bone osteocyte-Y4 (MLO-Y4) cells, were exposed to continuous compressive force and static tensile force. RESULTS: The relative quantification of immunodetection showed that orthodontic tooth movement significantly stimulated the Wnt1 expression in both the PDL and alveolar osteocytes on the tension side on day 5, whereas the expression on the compression side did not change. This increase in the Wnt1 expression, shown in vivo, was also noted after the application of 12% static tensile force in isolated hPDL fibroblasts and 20% in MLO-Y4 cells. In contrast, a compressive force led to the attenuation of the Wnt1 gene expression in both hPDL fibroblasts and MLO-Y4 cells in a force-dependent manner. In the osteocyte-PDL coculture system, recombinant sclerostin attenuated Wnt1 in PDL, whereas the antisclerostin antibody upregulated its gene expression, indicating that mechanically-driven Wnt1 signaling in PDL might be regulated by osteocytic sclerostin. CONCLUSIONS: Our findings provide that Wnt1 signaling plays a vital role in tooth movement-initiated bone remodeling via innovative mechanotransduction approaches.

Molecular Structure of Glycogen in Escherichia coli.

Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small ß particles which in animals bind to form composite α particles, which give better glucose release. Simulations imply ß particle size is controlled only by activities and sizes of glycogen biosynthetic enzymes and sizes of polymer chains. Thus, storing more glucose requires forming more ß particles, which are expected to sometimes form α particles. No α particles have been reported in bacteria, but the extraction techniques might have caused degradation. Using milder glycogen extraction techniques on Escherichia coli, transmission electron microscopy and size-exclusion chromatography showed α particles, consistent with this hypothesis for α-particle formation. Molecular density and size distributions show similarities with animal glycogen, despite very different metabolic processes. These general polymer constraints are such that any organism which needs to store and then release glucose will have similar α and ß particle structures: a type of convergent evolution.

Rapid Purification of dsRNA Using Micro-Spin Cellulose Column.

Double-stranded RNA (dsRNA) is the replication intermediates of all RNA viruses. Purification and analysis of the profile and sequence of dsRNA is vital in virus diagnoses and/or characterization. Cellulose is one of the common materials used for isolation of dsRNA. Cellulose specifically binds dsRNA fraction under 15% ethanol concentration, which allows to isolate dsRNA from total nucleic acid solution or cell lysate. Here, we describe a rapid and reliable method for purifying dsRNA using a home-made micro-spin cellulose column from the cell lysate of virus-infected plant tissue. This labor-saving and rapid method enables routinely high-throughput isolation and analysis of dsRNA in plant or fungi samples.

Exploring the Regulators of Keratinization: Role of BMP-2 in Oral Mucosa.

The oral mucosa functions as a physico-chemical and immune barrier to external stimuli, and an adequate width of the keratinized mucosa around the teeth or implants is crucial to maintaining them in a healthy and stable condition. In this study, for the first time, bulk RNA-seq analysis was performed to explore the gene expression of laser microdissected epithelium and lamina propria from mice, aiming to investigate the differences between keratinized and non-keratinized oral mucosa. Based on the differentially expressed genes (DEGs) and Gene Ontology (GO) Enrichment Analysis, bone morphogenetic protein 2 (BMP-2) was identified to be a potential regulator of oral mucosal keratinization. Monoculture and epithelial-mesenchymal cell co-culture models in the air-liquid interface (ALI) indicated that BMP-2 has direct and positive effects on epithelial keratinization and proliferation. We further performed bulk RNA-seq of the ALI monoculture stimulated with BMP-2 in an attempt to identify the downstream factors promoting epithelial keratinization and proliferation. Analysis of the DEGs identified, among others, IGF2, ID1, LTBP1, LOX, SERPINE1, IL24, and MMP1 as key factors. In summary, these results revealed the involvement of a well-known growth factor responsible for bone development, BMP-2, in the mechanism of oral mucosal keratinization and proliferation, and pointed out the possible downstream genes involved in this mechanism.

Bionic Bilayer Scaffold for Synchronous Hyperthermia Therapy of Orthotopic Osteosarcoma and Osteochondral Regeneration.

Large osseous void, postsurgical neoplastic recurrence, and slow bone-cartilage repair rate raise an imperative need to develop functional scaffold in clinical osteosarcoma treatment. Herein, a bionic bilayer scaffold constituting croconaine dye-polyethylene glycol@sodium alginate hydrogel and poly(l-lactide)/hydroxyapatite polymer matrix is fabricated to simultaneously achieve a highly efficient killing of osteosarcoma and an accelerated osteochondral regeneration. First, biomimetic osteochondral structure along with adequate interfacial interaction of the bilayer scaffold provide a structural reinforcement for transverse osseointegration and osteochondral regeneration, as evidenced by upregulated specific expressions of collagen type-I, osteopontin, and runt-related transcription factor 2. Meanwhile, thermal ablation of the synthesized nanoparticles and mitochondrial dysfunction caused by continuously released hydroxyapatite induce residual tumor necrosis synergistically. To validate the capabilities of inhibiting tumor growth and promoting osteochondral regeneration of our proposed scaffold, a novel orthotopic osteosarcoma model simulating clinical treatment scenarios of bone tumors is established on rats. Based on amounts of in vitro and in vivo results, an effective killing of osteosarcoma and a suitable osteal-microenvironment modulation of such bionic bilayer composite scaffold are achieved, which provides insightful implications for photonic hyperthermia therapy against osteosarcoma and following osseous tissue regeneration.

Ruxolitinib altered IFN-ß induced necroptosis of human dental pulp stem cells during osteoblast differentiation.

OBJECTIVE: This study aimed to evaluate the role of ruxolitinib in the interferon beta (IFN-ß) mediated osteoblast differentiation using human dental pulp stem cells (hDPSCs). DESIGN: hDPSCs from five deciduous teeth of healthy patients were stimulated by adding human recombinant IFN-ß protein (1 or 2 ng/ml) to the osteogenic differentiation induction medium. Substrate formation was determined using Alizarin Red staining, calcium concentration, and osteoblast marker expression levels. Ruxolitinib was used to inhibit the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway. Apoptosis was detected using terminal deoxynucleotidyl nick-end labeling (TUNEL) staining, and necroptosis was detected using propidium iodide staining and phosphorylated mixed lineage kinase domain-like protein (pMLKL) expression. RESULTS: In the IFN-ß-treated group, substrate formation was inhibited by a reduction in alkaline phosphatase (ALP) expression in a concentration-dependent manner. Although the proliferation potency was unchanged between the IFN-ß-treated and control groups, the cell number was significantly reduced in the experimental group. TUNEL-positive cell number was not significantly different; however, the protein level of necroptosis markers, interleukin-6 (IL-6) and pMLKL were significantly increased in the substrate formation. Cell number and ALP expression level were improved in the group administered ruxolitinib, a JAK-STAT inhibitor. Additionally, ruxolitinib significantly suppressed IL-6 and pMLKL levels. CONCLUSION: Ruxolitinib interfered with the IFN-ß-mediated necroptosis and osteogenic differentiation via the JAK-STAT pathway.

Tumor polyamines as guest cues attract host-functionalized liposomes for targeting and hunting via a bio-orthogonal supramolecular strategy.

Inspired by the attractions of fruit flies to polyamines of rotten food, we developed a facile, bio-orthogonal, supramolecular homing and hunting strategy, relying on the elevated levels of polyamines in tumor as the natural guest cues to attract cucurbit [7] uril (CB[7]) functionalized liposomes to the tumor site, owing to the strong, bio-orthogonal host-guest interactions between CB[7] and polyamines. This supramolecular homing enabled a high targeting efficiency of CB[7] functionalized liposomes, and allowed better tissue penetration and retention in breast tumor. The employment of a receptor functionalized nanomedicine for direct tropism towards endogenous biomarkers as guest cues, reminiscent of natural chemotaxis but in a bio-orthogonal manner, has not been previously reported, offering new sights to the design and development of new nanoformulations that rely on bio-orthogonal interactions for chemotaxis-guided targeting.

Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity.

Osteoarthritis is a degenerative joint disease that causes pain, degradation, and dysfunction. Excessive canonical Wnt signaling in osteoarthritis contributes to chondrocyte phenotypic instability and loss of cartilage homeostasis; however, the regulatory niche is unknown. Using the temporomandibular joint as a model in multiple species, we identify Lgr5-expressing secretory cells as forming a Wnt inhibitory niche that instruct Wnt-inactive chondroprogenitors to form the nascent synovial joint and regulate chondrocyte lineage and identity. Lgr5 ablation or suppression during joint development, aging, or osteoarthritis results in depletion of Wnt-inactive chondroprogenitors and a surge of Wnt-activated, phenotypically unstable chondrocytes with osteoblast-like properties. We recapitulate the cartilage niche and create StemJEL, an injectable hydrogel therapy combining hyaluronic acid and sclerostin. Local delivery of StemJEL to post-traumatic osteoarthritic jaw and knee joints in rabbit, rat, and mini-pig models restores cartilage homeostasis, chondrocyte identity, and joint function. We provide proof of principal that StemJEL preserves the chondrocyte niche and alleviates osteoarthritis.

From vaccines to nanovaccines: A promising strategy to revolutionize rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a joint-related autoimmune disease that is difficult to cure. Most therapeutics act to alleviate the symptoms but not correct the causes of RA. Novel strategies that specifically target the causes are highly needed for RA management. Currently, early interruption of RA is increasingly suggested but the corresponding therapeutics are not available. Vaccines that have shown great success to combat infection, cancer, degenerative diseases, autoimmune diseases, etc. are ideal candidates for a new generation of anti-RA therapeutics to correct the causes and prevent RA or interrupt RA in early phases. Anti-RA vaccines can be divided into two major categories. One is to induce neutralizing antibodies and the other is to induce antigen-specific immune tolerance. The vaccines are inherently linked to nanotechnology because they usually need a biomacromolecule or carrier to provoke sufficient immune responses. In the past decade, designed nanocarriers such as nanoparticles, liposomes, nanoemulsion, etc., have been applied to optimize the vaccines for autoimmune disease treatment. Nanotechnology endows vaccines with a higher biostability, tunable in vivo behavior, better targeting, co-delivery with stimulatory agents, regulatory effects on immune responses, etc. In this review, unmet medical needs for RA treatment and anti-RA vaccinology are first introduced. The development of anti-RA therapies from vaccines to nanovaccines are then reviewed and perspectives on how nanotechnology promotes vaccine development and advancement are finally provided. In addition, challenges for anti-RA vaccine development are summarized and advantages of nanovaccines are analyzed. In conclusion, nanovaccines will be a promising strategy to revolutionize the treatment of RA by correcting the causes in an early phase of RA.

Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia.

Acute pneumonia is an inflammatory syndrome often associated with severe multi-organ dysfunction and high mortality. The therapeutic efficacy of current anti-inflammatory medicines is greatly limited due to the short systemic circulation and poor specificity in the lungs. New drug delivery systems (DDS) are urgently needed to efficiently transport anti-inflammatory drugs to the lungs. Here, we report an inflammation-responsive supramolecular erythrocytes-hitchhiking DDS to extend systemic circulation of the nanomedicine via hitchhiking red blood cells (RBCs) and specifically "drop off" the payloads in the inflammatory lungs. ß-cyclodextrin (ß-CD) modified RBCs and ferrocene (Fc) modified liposomes (NP) were prepared and co-incubated to attach NP to RBCs via ß-CD/Fc host-guest interactions. RBCs extended the systemic circulation of the attached NP, meanwhile, the NP may get detached from RBCs due to the high ROS level in the inflammatory lungs. In acute pneumonia mice, this strategy delivered curcumin specifically to the lungs and effectively alleviated the inflammatory syndrome.

Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis.

Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR-/- mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with µCT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.

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The primary hydrogen (H) source for all organic compounds in the biosphere is from water, and then participates in biogeochemical cycles through photosynthesis and plant physiological metabolism. As a new proxy of paleoclimate and paleoenvironment, stable hydrogen isotope ratios in wood lignin methoxyl groups (δ2HLM) show great advantages in the studies of paleoclimatic change and have been used to reconstruct precipitation stable hydrogen isotope ratios and paleoclimate signals in many regions. Based on the lignin application mechanism and analysis method of δ2HLM, we evaluated the stability and effectiveness of δ2HLM-measurement method from lignin content and lignin monomer composition, and expounded the tree lignin methoxyl groups' stable isotope proxies of current research outcomes. In the middle latitudes, the tree-ring δ2HLM had great potential in recording temperature signals and precipitation stable hydrogen isotope ratios. However, the study of tree-ring δ2HLM was still in its infancy as evidenced by following reasons: 1) The study area was limited to the middle latitude of the northern hemisphere, and the study subjects were limited to conifer species; 2) To compensate for the limitation of hydrogen isotopic records of nitrocellulose, high resolution tree-ring δ2HLM would be studied; 3) The potential of tree-ring δ2HLM utilization in plant physiology and forest ecology remained to be exploited.

Next-Generation Sequencing Technologies and Neurogenetic Diseases.

Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot-Marie-Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.