Osteopetrosis-like disorders induced by osteoblast-specific retinoic acid signaling inhibition in mice.

Osteopetrosis is an inherited metabolic disease, characterized by increased bone density and narrow marrow cavity. Patients with severe osteopetrosis exhibit abnormal bone brittleness, anemia, and infection complications, which commonly cause death within the first decade of life. Pathologically, osteopetrosis impairs not only the skeletal system, but also the hemopoietic and immune systems during development, while the underlying osteoimmunological mechanisms remain unclear. Osteoclastic mutations are regarded as the major causes of osteopetrosis, while osteoclast non-autonomous theories have been proposed in recent years with unclear underlying mechanisms. Retinoic acid (RA), the metabolite of Vitamin A, is an essential requirement for skeletal and hematopoietic development, through the activation of retinoic acid signaling. RA can relieve osteopetrosis symptoms in some animal models, while its effect on bone health is still controversial and the underlying mechanisms remain unclear. In this study, we constructed an osteoblast-specific inhibitory retinoic acid signaling mouse model and surprisingly found it mimicked the symptoms of osteopetrosis found in clinical cases: dwarfism, increased imperfectly-formed trabecular bone deposition with a reduced marrow cavity, thin cortical bone with a brittle skeleton, and hematopoietic and immune dysfunction. Micro-CT, the three-point bending test, and histological analysis drew a landscape of poor bone quality. Single-cell RNA sequencing (scRNA-seq) of the femur and RNA-seq of osteoblasts uncovered an atlas of pathological skeletal metabolism dysfunction in the mutant mice showing that osteogenesis was impaired in a cell-autonomous manner and osteoclastogenesis was impaired via osteoblast-osteoclast crosstalk. Moreover, scRNA-seq of bone marrow and flow cytometry of peripheral blood, spleen, and bone marrow uncovered pathology in the hematopoietic and immune systems in the mutant mice, mimicking human osteopetrosis. Results showed that hematopoietic progenitors and B lymphocyte differentiation were affected and the osteoblast-dominated cell crosstalk was impaired, which may result from transcriptional impairment of the ligands Pdgfd and Sema4d. In summary, we uncovered previously unreported pathogenesis of osteopetrosis-like disorder in mice with skeletal, hematopoietic, and immune system dysfunction, which was induced by the inhibition of retinoic acid signaling in osteoblasts, and sheds new insights into a potential treatment for osteopetrosis.

Variation of Odontoid Incidence According to Age in Asymptomatic Children.

OBJECTIVE: To investigate the effect of age and sex on odontoid parameters and their relationships with cervical sagittal alignment in children. METHODS: A total of 155 Chinese children without cervical symptoms were divided into groups by age: 3-12 years (87 participants), 13-18 years (68 participants), and sex: male (91 participants) and female (64 participants). Lateral plain radiographs of the whole spine were analyzed for (1) odontoid parameters: odontoid incidence (OI), odontoid tilt, and C2 slope (C2S); and (2) cervical sagittal parameters: C0-2, C2-3, C2-4, C2-5, C2-6, and C2-7 angles (cervical lordosis [CL]), T1 slope (T1S), and T1S minus CL (T1S-CL). Student's t-tests, linear regression analyses, and Pearson's correlation coefficient analyses were performed. RESULTS: OI showed a significant difference between the 3-12 and 13-18 year groups (13.35°±4.32° vs. 17.21°±4.26°, P<0.001), and significant differences were also observed in odontoid tilt (P=0.001) and C2S (P<0.001) between different sexes. Positive correlations were found between age and OI in the 3-12 and 13-18 year groups (adjusted R2=0.104 and 0.048, respectively). OI and C2S were positively correlated with the C0-2 angle in all age and sex groups. CONCLUSIONS: Age emerged as a critical determinant of OI, which increased with age among pediatric populations. Clinicians should carefully consider the disparity in OI during the assessment and restoration of cervical sagittal balance in children.

Therapy management and outcome of acute hydrocephalus secondary to intraventricular hemorrhage in adults.

BACKGROUND: Intraventricular hemorrhage (IVH) refers to bleeding within the brain's ventricular system, and hydrocephalus is a life-threatening complication of IVH characterized by increased cerebrospinal fluid accumulation in the ventricles resulting in elevated intracranial pressure. IVH poses significant challenges for healthcare providers due to the complexity of the underlying pathophysiology and lack of standardized treatment guidelines. Herein, we performed a systematic review of the treatment strategies for hydrocephalus secondary to IVH. METHODS: This systematic review was prospectively registered with PROSPERO (CRD42023450786). The search was conducted in PubMed, Cochrane Library, and Web of Science on July 15, 2023. We included original studies containing valid information on therapy management and outcome of hydrocephalus secondary to primary, spontaneous, and subarachnoid or intracranial hemorrhage following IVH in adults that were published between 2000 and 2023. Glasgow Outcome Scale (GOS) or modified Ranking Scale (mRS) scores during follow-up were extracted as primary outcomes. The risk of bias was assessed using the Newcastle-Ottawa Scale for Cohort Studies or Cochrane Risk of Bias 2.0 Tool. RESULTS: Two hundred and seven patients from nine published papers, including two randomized controlled trials, were included in the analysis. The GOS was used in five studies, while the mRS was used in four. Seven interventions were applied, including craniotomy for removal of hematoma, endoscopic removal of hematoma with/without endoscopic third ventriculostomy (ETV), traditional external ventricular drainage (EVD), and various combinations of EVD, lumbar drainage (LD), and intraventricular fibrinolysis (IVF). Endoscopic removal of hematoma was performed in five of nine studies. Traditional EVD had no obvious benefit compared with new management strategies. Three different combinations of EVD, LD, and IVF demonstrated satisfactory outcomes, although more studies are required to confirm their reliability. Removal of hematoma through craniotomy generated reliable result. Generally, endoscopic removal of hematoma with ETV, removal of hematoma through craniotomy, EVD with IVF, and EVD with early continuous LD were useful. CONCLUSION: EVD is still crucial for the management of IVH and hydrocephalus. Despite a more reliable result from the removal of hematoma through craniotomy, a trend toward endoscopic approach was observed due to a less invasive profile.

Calycosin action against atherosclerosis: integrating network pharmacology and in-silico investigation.

Atherosclerosis, caused by lipid deposit in the arterial wall for narrowing the arteries, is an increased risk factor of developing heart failure. Presently, clinical first-line drug therapy can be found with side effects, and thus new substitute medication should be developed needfully. Calycosin is one of the most bioactive products refined from natural plant, and it exerts promising cardiovascular protective effect. However, the pharmacological mechanisms of calycosin against atherosclerosis have not been elaborated. In this study, a systematic network pharmacology combined with molecular docking analysis was used to reveal the interaction activity and biological target in calycosin against atherosclerosis. We screened all preparative targets linked to calycosin and atherosclerosis from the available public databases. These results indicated total 409 putative targets in calycosin action, 71 of which were interacted with atherosclerosis. Further biological docking analysis suggested that calycosin displayed the powerful binding affinities with target proteins, including interleukin-6 (IL6) and mitogen-activated protein kinase 3 (MAPK3) MAPK3. Then enrichment findings revealed that calycosin action to treat atherosclerosis might be related to inhibition of inflammatory reaction and oxidative stress through modulating nucleolus transcription factor for improving lipid metabolism. In conclusion, the anti-atherosclerotic targets and molecular mechanisms in calycosin action were revealed systematically through preclinical evaluation. And calycosin may be a potential natural compound for the treatment of atherosclerosis.

Occlusal force orchestrates alveolar bone homeostasis via Piezo1 in female mice.

Healthy alveolar bone is the cornerstone of oral function and oral treatment. Alveolar bone is highly dynamic during the entire lifespan and is affected by both systemic and local factors. Importantly, alveolar bone is subjected to unique occlusal force in daily life, and mechanical force is a powerful trigger of bone remodeling, but the effect of occlusal force in maintaining alveolar bone mass remains ambiguous. In this study, the Piezo1 channel is identified as an occlusal force sensor. Activation of Piezo1 rescues alveolar bone loss caused by a loss of occlusal force. Moreover, we identify Piezo1 as the mediator of occlusal force in osteoblasts, maintaining alveolar bone homeostasis by directly promoting osteogenesis and by sequentially regulating catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. Interestingly, Piezo1 activation also exhibits remarkable efficacy in the treatment of alveolar bone osteoporosis caused by estrogen deficiency, which is highly prevalent among middle-aged and elderly women. Promisingly, Piezo1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.

Daily occlusal force and estrogen synergistically maintain alveolar bone homeostasis. PIEZO1 in osteoblasts plays a critical role in sensing occlusal force and maintaining bone mass. PIEZO1 may promote osteoclastic apoptosis through osteoblast-secreted FasL through a PIEZO1-STAT3/ESR1-FasL pathway. Restoration of occlusal force with dental therapies as early as possible to prevent alveolar bone loss is the major priority in oral health care. PIEZO1 may serve as a potential target for bone metabolism disorders.

Elevated SLC7A2 expression is associated with an abnormal neuroinflammatory response and nitrosative stress in Huntington's disease.

We previously identified solute carrier family 7 member 2 (SLC7A2) as one of the top upregulated genes when normal Huntingtin was deleted. SLC7A2 has a high affinity for L-arginine. Arginine is implicated in inflammatory responses, and SLC7A2 is an important regulator of innate and adaptive immunity in macrophages. Although neuroinflammation is clearly demonstrated in animal models and patients with Huntington's disease (HD), the question of whether neuroinflammation actively participates in HD pathogenesis is a topic of ongoing research and debate. Here, we studied the role of SLC7A2 in mediating the neuroinflammatory stress response in HD cells. RNA sequencing (RNA-seq), quantitative RT-PCR and data mining of publicly available RNA-seq datasets of human patients were performed to assess the levels of SLC7A2 mRNA in different HD cellular models and patients. Biochemical studies were then conducted on cell lines and primary mouse astrocytes to investigate arginine metabolism and nitrosative stress in response to neuroinflammation. The CRISPR-Cas9 system was used to knock out SLC7A2 in STHdhQ7 and Q111 cells to investigate its role in mediating the neuroinflammatory response. Live-cell imaging was used to measure mitochondrial dynamics. Finally, exploratory studies were performed using the Enroll-HD periodic human patient dataset to analyze the effect of arginine supplements on HD progression. We found that SLC7A2 is selectively upregulated in HD cellular models and patients. HD cells exhibit an overactive response to neuroinflammatory challenges, as demonstrated by abnormally high iNOS induction and NO production, leading to increased protein nitrosylation. Depleting extracellular Arg or knocking out SLC7A2 blocked iNOS induction and NO production in STHdhQ111 cells. We further examined the functional impact of protein nitrosylation on a well-documented protein target, DRP-1, and found that more mitochondria were fragmented in challenged STHdhQ111 cells. Last, analysis of Enroll-HD datasets suggested that HD patients taking arginine supplements progressed more rapidly than others. Our data suggest a novel pathway that links arginine uptake to nitrosative stress via upregulation of SLC7A2 in the pathogenesis and progression of HD. This further implies that arginine supplements may potentially pose a greater risk to HD patients.

Odontoid incidence: a constant cervical anatomical feature evident in standing plain radiographs and supine magnetic resonance images.

OBJECTIVE: To assess whether there is a difference between measurements of odontoid incidence (OI) and other cervical sagittal parameters by X-ray radiography and those by supine magnetic resonance imaging (MRI). METHODS: Standing X-ray and supine MRI images of 42 healthy subjects were retrospectively analyzed. Surgimap software was employed to measure cervical sagittal parameters including OI, odontoid tilt (OT), C2 slope (C2S), C0-2 angle, C2-7 angle, T1 slope (T1S) and T1S-cervical lordosis (CL). Paired samples t-test was applied to determine the difference between parameters measured by standing X-ray and those by supine MRI. In addition, the statistical correlation between the parameters were compared. The prediction of CL was performed and validated using the formula CL = 0.36 × OI - 0.67 × OT - 0.69 × T1S. RESULTS: Significant correlations and differences were found between cervical sagittal parameters determined by X-ray and those by MRI. OI was verified to be a constant anatomic parameter and the formula CL = 0.36 × OI - 0.67 × OT - 0.69 × T1S can be used to predict CL in cervical sagittal parameters. CONCLUSIONS: OI is verified as a constant anatomic parameter, demonstrating the necessity of a combined assessment of cervical sagittal balance by using standing X-ray and supine MRI. The formula CL = 0.36 × OI - 0.67 × OT - 0.69 × T1S can be applied to predict CL in cervical sagittal parameters.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.

Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration Via Engineered Extracellular Vesicles.

Overactivated inflammatory reactions hinder the bone regeneration process. Timely transformation of microenvironment from pro-inflammatory to anti-inflammatory after acute immune response is favorable for osteogenesis. Macrophages play an important role in the immune response to inflammation. Therefore, this study adopts TIM3 high expression extracellular vesicles (EVs) with immunosuppressive function to reshape the early immune microenvironment of bone injury, mainly by targeting macrophages. These EVs can be phagocytosed by macrophages, thereby increasing the infiltration of TIM3-positive macrophages (TIM3+ macrophages) and M2 subtypes. The TIM3+ macrophage group has some characteristics of M2 macrophages and secretes cytokines, such as IL-10 and TGF-ß1 to regulate inflammation. TIM3, which is highly expressed in the engineered EVs, mediates the release of anti-inflammatory cytokines by inhibiting the p38/MAPK pathway and promotes osseointegration by activating the Bmp2 promoter to enhance macrophage BMP2 secretion. After evenly loading the engineered EVs into the hydrogel, the continuous and slow release of EVsTIM3OE recruits more anti-inflammatory macrophages during the early stages of bone defect repair, regulating the immune microenvironment and eliminating the adverse effects of excessive inflammation. In summary, this study provides a new strategy for the treatment of refractory wounds through early inflammation control.

A Facilely Synthesized NiCo2S4 with Two Mutually Reinforcing Active Sites for High-Performance Lithium-Sulfur Batteries.

The shuttle effect and slow conversion kinetics of soluble polysulfides hinder the commercial application of lithium-sulfur batteries (LSBs). In this context, we propose a three-dimensional lamellar-stacked nanostructure of nickel cobalt sulfide (D-NiCo2S4) enriched with lattice defects by manipulating the cations in spinel sulfides. It has an obvious synergistic promotion mechanism for the adsorption and catalysis of lithium sulfides. Specifically, Ni3+ on tetrahedral (Td) sites with strong Ni-S covalency anchors LiPSs, whereas Co3+ on octahedral (Oh) sites promotes a highly efficient catalytic conversion of LiPSs, which is confirmed by experimental results and density functional theory (DFT) calculations. Besides, the crystal defects and distortions in the lamellar region could expose more active sites and enhance the redox reaction kinetics of polysulfides. Hence, Li-S batteries with D-NiCo2S4@S as the cathode show outstanding cycle stability; upon cycling at 1 A/g, the battery achieves a high initial specific capacity of 1001.12 and 655.31 mAh g-1 after 1000 cycles (decay rate as low as 0.05% per cycle), as well as a high initial areal capacity of 3.15 mAh cm-2 under high S loading (4.2 mg cm-2). This work provides a viable scheme for designing efficient bimetal sulfide catalysts and furnishes a rational strategy for constructing LSB cathodes with high specific capacity and high area capacity.

The odontoblastic differentiation of dental mesenchymal stem cells: molecular regulation mechanism and related genetic syndromes.

Dental mesenchymal stem cells (DMSCs) are multipotent progenitor cells that can differentiate into multiple lineages including odontoblasts, osteoblasts, chondrocytes, neural cells, myocytes, cardiomyocytes, adipocytes, endothelial cells, melanocytes, and hepatocytes. Odontoblastic differentiation of DMSCs is pivotal in dentinogenesis, a delicate and dynamic process regulated at the molecular level by signaling pathways, transcription factors, and posttranscriptional and epigenetic regulation. Mutations or dysregulation of related genes may contribute to genetic diseases with dentin defects caused by impaired odontoblastic differentiation, including tricho-dento-osseous (TDO) syndrome, X-linked hypophosphatemic rickets (XLH), Raine syndrome (RS), hypophosphatasia (HPP), Schimke immuno-osseous dysplasia (SIOD), and Elsahy-Waters syndrome (EWS). Herein, recent progress in the molecular regulation of the odontoblastic differentiation of DMSCs is summarized. In addition, genetic syndromes associated with disorders of odontoblastic differentiation of DMSCs are discussed. An improved understanding of the molecular regulation and related genetic syndromes may help clinicians better understand the etiology and pathogenesis of dentin lesions in systematic diseases and identify novel treatment targets.

Amplitude-Modulated Electrodeformation to Evaluate Mechanical Fatigue of Biological Cells.

Red blood cells (RBCs) are known for their remarkable deformability. They repeatedly undergo considerable deformation when passing through the microcirculation. Reduced deformability is seen in physiologically aged RBCs. Existing techniques to measure cell deformability cannot easily be used for measuring fatigue, the gradual degradation in cell membranes caused by cyclic loads. We present a protocol to evaluate mechanical degradation in RBCs from cyclic shear stresses using amplitude shift keying (ASK) modulation-based electrodeformation in a microfluidic channel. Briefly, the interdigitated electrodes in the microfluidic channel are excited with a low voltage alternating current at radio frequencies using a signal generator. RBCs in suspension respond to the electric field and exhibit positive dielectrophoresis (DEP), which moves cells to the electrode edges. Cells are then stretched due to the electrical forces exerted on the two cell halves, resulting in uniaxial stretching, known as electrodeformation. The level of shear stress and the resultant deformation can be easily adjusted by changing the amplitude of the excitation wave. This enables quantifications of nonlinear deformability of RBCs in response to small and large deformations at high throughput. Modifying the excitation wave with the ASK strategy induces cyclic electrodeformation with programmable loading rates and frequencies. This provides a convenient way for the characterization of RBC fatigue. Our ASK-modulated electrodeformation approach enables, for the first time, a direct measurement of RBC fatigue from cyclic loads. It can be used as a tool for general biomechanical testing, for analyses of cell deformability and fatigue in other cell types and diseased conditions, and can also be combined with strategies to control the microenvironment of cells, such as oxygen tension and biological and chemical cues.

Using Inducible Osteoblastic Lineage-Specific Stat3 Knockout Mice to Study Alveolar Bone Remodeling During Orthodontic Tooth Movement.

The alveolar bone, with a high turnover rate, is the most actively-remodeling bone in the body. Orthodontic tooth movement (OTM) is a common artificial process of alveolar bone remodeling in response to mechanical force, but the underlying mechanism remains elusive. Previous studies have been unable to reveal the precise mechanism of bone remodeling in any time and space due to animal model-related restrictions. The signal transducer and activator of transcription 3 (STAT3) is important in bone metabolism, but its role in osteoblasts during OTM is unclear. To provide in vivo evidence that STAT3 participates in OTM at specific time points and in particular cells during OTM, we generated a tamoxifen-inducible osteoblast lineage-specific Stat3 knockout mouse model, applied orthodontic force, and analyzed the alveolar bone phenotype. Micro-computed tomography (Micro-CT) and stereo microscopy were used to access OTM distance. Histological analysis selected the area located within three roots of the first molar (M1) in the cross-section of the maxillary bone as the region of interest (ROI) to evaluate the metabolic activity of osteoblasts and osteoclasts, indicating the effect of orthodontic force on alveolar bone. In short, we provide a protocol for using inducible osteoblast lineage-specific Stat3 knockout mice to study bone remodeling under orthodontic force and describe methods for analyzing alveolar bone remodeling during OTM, thus shedding new light on skeletal mechanical biology.

Scientific publications on orthopedic surgery from three major East Asian countries (2012-2021).

BACKGROUND: East Asia is the most dynamic region in the world and includes three major countries: Japan, South Korea and China. Due to rapid economic growth, orthopedics research in East Asia has achieved great advances during the past 10 years. However, the current status of orthopedic research in Japan, South Korea and China is still unclear. AIM: To understand the current status of orthopedic research in Japan, South Korea, and China. METHODS: Journals listed in the ''Orthopedics'' category of Science Citation Index Expanded subject categories were included. The PubMed and Web of Knowledge electronic databases were searched to identify scientific publications from the selected journals written by researchers from Japan, South Korea and China. A systematic analysis was conducted to analyze orthopedic research articles published in the three countries based on the number of articles, study design, impact factors (IFs) and citations. Furthermore, we also ranked the top 10 countries worldwide with the highest publications in the past 10 years. Additionally, we ranked the top 10 countries with the highest number of publications in the world in the past 10 years. Statistical analyses were performed using SPSS 20.0 software (SPSS Inc., Chicago, IL, United States), and statistical results are given in Tables and Figures. The Kruskal-Wallis test and the Mann-Whitney test were used to detect differences between countries. The tendency regarding the number of articles was analyzed by curvilinear regression. A two-tailed P < 0.05 was considered significant. RESULTS: From 2012-2021, a total of 144518 articles were published in the 86 selected orthopedic journals. During this period, the number of worldwide published orthopedic articles has shown an annual increasing trend. A total of 27164 orthopedic research articles were published by Japan, South Korea and China during the past 10 years; 44.32% were from China, 32.98% were from Japan, and 22.70% were from South Korea. From 2012 to 2021, the annual number of articles markedly increased in each of the three countries. Over time, the worldwide share of articles increased substantially in South Korea (3.37% to 6.53%, P < 0.001) and China (5.29% to 9.61%, P < 0.001). However, the worldwide share of articles significantly decreased in Japan (5.22% to 3.80%, P < 0.001). The annual total IFs of articles from China were well above those of articles from Japan and South Korea (36597.69 vs 27244.48 vs 20657.83, P < 0.05). There was no significant difference among the articles in the top 10 high-IF orthopedics journals published from those three countries [South Korea (800) > China (787) > Japan (646), P > 0.05]. CONCLUSION: Over the past 10 years, China's scientific publications in orthopedic journals have shown an increasing trend. Considering the relative scale of the populations, Japan and South Korea have outpaced China with respect to quality.

The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia.

Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed. Key proteins involved in apoptosis, endoplasmic reticulum (ER) stress, and heat shock proteins were analyzed using immunoblotting. Carb is effective in protecting PC12 cells against glutamate- or hypoxia-induced cell injury. Electrophysiological results show that Carb attenuates NMDA-mediated glutamate currents in the retinal ganglion cells, which results in activation of the AKT signaling pathway and increased expression of pro-cell survival biomarkers, e.g., Hsp 27, P-AKT, and Bcl2 and decreased expression of pro-cell death markers, e.g., Beclin 1, Bax, and Cleaved caspase 3, and ER stress markers, e.g., CHOP, IRE1, XBP1, ATF 4, and eIF2α. Using the BCAO animal stroke model, we found that Carb reduced the brain infarct volume and decreased levels of ER stress markers, GRP 78, CHOP, and at the behavioral level, e.g., a decrease in asymmetric turns and an increase in locomotor activity. These findings for Carb provide promising and rational strategies for stroke therapy.

Cobalt nanoparticles & nitrogen-doped carbon nanotubes@hollow carbon with high catalytic ability for high-performance lithium sulfur batteries.

Lithium-sulfur (Li-S) battery has been considered as a potential next-era energy storage device. However, its practical application is limited by the volume change of sulfur and the shuttle effect of lithium polysulfides. To effectively overcome these issues, a hollow carbon decorated with cobalt nanoparticles and interconnected by nitrogen doped carbon nanotubes (Co-NCNT@HC) is developed for high-performance Li-S battery. The uniformly distributed nitrogen and cobalt nanoparticles in Co-NCNT@HC are able to enhance the chemical adsorption capability and fasten the transformation speed of the intermediates, thus effectively inhibit the loss of lithium polysulfides. Moreover, the hollow carbon spheres interconnected by carbon nanotubes are structurally stable and electrically conductive. Due to the unique structure, the Li-S battery enhanced by Co-NCNT@HC shows a high initial capacity of 1550 mAh/g at 0.1 A g-1. Even at a high current density of 2.0 A g-1, after 1000 cycles, it still maintains a capacity of 750 mAh/g with a capacity retention of 76.4% (the capacity decay rate is only 0.037% per cycle). This study provides a promising strategy for the development of high-performance Li-S batteries.

Exercise maintains bone homeostasis by promoting osteogenesis through STAT3.

Bone exhibits changes in density, strength, and microarchitecture in relation to mechanical loading mediated by exercise. Appropriate exercise maintains bone homeostasis, while the absence of exercise leads to disuse bone loss. However, the acting mechanism of mechanotransduction in bone remains unclear. We performed the running-wheel exercise and tail suspension model to study the effects of exercise on bone metabolism, and found that osteoblastic Signal transducer and activator of transcription 3 (STAT3) activity was closely related to exercise-induced bone mass and metabolism changes. With the Flexcell tension-loading system in vitro, mechanical force promoted STAT3 activity, which was accompanied by increased osteoblastic differentiation of the bone marrow mesenchymal stem cells (BMSCs). In contrast, the inhibition of STAT3 phosphorylation blocked force-induced osteoblastic differentiation. Furthermore, pharmacological inactivation of STAT3 impaired the increase in exercise-induced bone mass and osteogenesis. With an inducible conditional deletion mouse model, we found that the osteoblast lineage-specific Stat3 deletion could also block force-induced osteoblastic differentiation in vitro and impair exercise-promoted bone mass and osteogenesis in vivo. This confirmed the crucial role of osteoblastic STAT3 in exercise-mediated bone metabolism. Finally, colivelin, a STAT3 agonist, promoted osteoblastic differentiation in vitro and partly rescued exercise loss-induced disuse bone loss by improving osteogenesis in the tail suspension model. Taken together, our study revealed the essential role of STAT3 in maintaining exercise-mediated bone homeostasis. In addition, STAT3 might act as a potential target for osteoporosis caused by exercise loss.

Sheet-on-sheet ZnIn2S4@RGO-modified separators with abundant sulfur vacancies for high-performance Li-S batteries.

A novel sheet-on-sheet architecture with abundant sulfur vacancies (Vs) is designed by in situ growth of flake-like ZnIn2S4 on the reduced graphene oxide (Vs-ZIS@RGO) surface, which serves as a functional layer on the separators for high-performance lithium-sulfur batteries (LSBs). Benefiting from the sheet-on-sheet architecture, the separators exhibit rapid ionic/electronic transfer, which is capable of supporting fast redox reactions. The vertically ordered ZnIn2S4 shortens the diffusion pathways of lithium-ions and the irregularly curved nanosheets expose more active sites to effectively anchor lithium polysulfides (LiPSs). More importantly, the introduction of Vs adjusts the surface or interface electronic structure of ZnIn2S4, enhancing the chemical affinity to LiPSs while accelerating conversion reaction kinetics of LiPSs. As expected, the batteries with Vs-ZIS@RGO modified separators exhibit an initial discharge capacity of 1067 mA h g-1 at 0.5C. Even at 1C, the excellent long cycle stability (710 mA h g-1 over 500 cycles) with an ultra-low decay rate of 0.055% per cycle is also attained. This work proposes a strategy of designing the sheet-on-sheet structure with rich sulfur vacancies, which provides a new perspective to rationally devise durable and efficient LSBs.

ScRNA-seq links dental fibroblasts heterogeneity with mechanoresponsiveness.

BACKGROUND AND OBJECTIVE: Periodontal ligament (PDL) and dental pulp (DP) share a common origin but have distinct biological and mechanical functions. To what extent the mechanoresponsive property of PDL can be attributed to its unique transcriptional profiles of cellular heterogeneity is unclear. This study aims to decipher cellular heterogeneity and distinct mechanoresponsive characteristics of odontogenic soft tissues and their underlying molecular mechanisms. MATERIALS AND METHODS: A single-cell comparison of digested human periodontal ligament (PDL) and dental pulp (DP) was performed using scRNA-seq. An in vitro loading model was constructed to measure mechanoresponsive ability. Dual-luciferase assay, overexpression, and shRNA knockdown were used to investigate the molecular mechanism. RESULTS: Our results demonstrate striking fibroblast heterogeneity across and within human PDL and DP. We demonstrated that a tissue-specific subset of fibroblasts existed in PDL exhibiting high expression of mechanoresponsive extracellular matrix (ECM) genes, which was verified by an in vitro loading model. ScRNA-seq analysis indicated a particularly enriched regulator in PDL-specific fibroblast subtype, Jun Dimerization Protein 2 (JDP2). Overexpression and knockdown of JDP2 extensively regulated the downstream mechanoresponsive ECM genes in human PDL cells. The force loading model demonstrated that JDP2 responded to tension and that knockdown of JDP2 effectively inhibited the mechanical force-induced ECM remodeling. CONCLUSIONS: Our study constructed the PDL and DP ScRNA-seq atlas to demonstrate PDL and DP fibroblast cellular heterogeneity and identify a PDL-specific mechanoresponsive fibroblast subtype and its underlying mechanism.