Oxysterol 25-hydroxycholesterol activation of ferritinophagy inhibits the development of squamous intraepithelial lesion of cervix in HPV-positive patients.

Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.

Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms.

Intervertebral disc degeneration is closely related to abnormal phenotypic changes in disc cells. However, the mechanism by which disc cell phenotypes are maintained remains poorly understood. Here, Hedgehog-responsive cells were found to be specifically localized in the inner annulus fibrosus and cartilaginous endplate of postnatal discs, likely activated by Indian Hedgehog. Global inhibition of Hedgehog signaling using a pharmacological inhibitor or Agc1-CreERT2-mediated deletion of Smo in disc cells of juvenile mice led to spontaneous degenerative changes in annulus fibrosus and cartilaginous endplate accompanied by aberrant disc cell differentiation in adult mice. In contrast, Krt19-CreER-mediated deletion of Smo specifically in nucleus pulposus cells led to healthy discs and normal disc cell phenotypes. Similarly, age-related degeneration of nucleus pulposus was accelerated by genetic inactivation of Hedgehog signaling in all disc cells, but not in nucleus pulposus cells. Furthermore, inactivation of Gli2 in disc cells resulted in partial loss of the vertebral growth plate but otherwise healthy discs, whereas deletion of Gli3 in disc cells largely corrected disc defects caused by Smo ablation in mice. Taken together, our findings not only revealed for the first time a direct role of Hedgehog-Gli3 signaling in maintaining homeostasis and cell phenotypes of annuls fibrosus and cartilaginous endplate, but also identified disc-intrinsic Hedgehog signaling as a novel non-cell-autonomous mechanism to regulate nucleus pulposus cell phenotype and protect mice from age-dependent nucleus pulposus degeneration. Thus, targeting Hedgehog signaling may represent a potential therapeutic strategy for the prevention and treatment of intervertebral disc degeneration.

Piperlongumine, a Piper longum-derived amide alkaloid, protects mice from ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis via suppression of p38 and JNK signaling.

Postmenopausal osteoporosis (PMOP) is a metabolic bone disease that results from overproduction and hyperactivation of osteoclasts caused by insufficient estrogen in women after menopause. Current therapeutic strategies are mainly focused on treating PMOP patients who have already developed severe bone loss or even osteoporotic fractures. Obviously, a better strategy is to prevent PMOP from occurring in the first place. However, such reagents are largely lacking. Piperlongumine (PLM), an amide alkaloid extracted from long pepper Piper longum, exhibits the anti-osteoclastogenic effect in normal bone marrow macrophages (BMMs) and the protective effect against osteolysis induced by titanium particles in mice. This study examined the preventive effect of PLM on PMOP and explored the potential mechanism of this effect using both ovariectomized mice and their primary cells. The result showed that PLM (5 and 10 mg kg-1) administered daily for 6 weeks ameliorated ovariectomy-induced bone loss and osteoclast formation in mice. Further cell experiments showed that PLM directly suppressed osteoclast formation, F-actin ring formation, and osteoclastic resorption pit formation in BMMs derived from osteoporotic mice, but did not obviously affect osteogenic differentiation of bone marrow stromal cells (BMSCs) from these mice. Western blot analysis revealed that PLM attenuated maximal activation of p38 and JNK pathways by RANKL stimulation without affecting acute activation of NF-κB, AKT, and ERK signaling. Furthermore, PLM inhibited expression of key osteoclastogenic transcription factors NFATc1/c-Fos and their target genes (Dcstamp, Atp6v0d2, Acp5, and Oscar). Taken together, our findings suggest that PLM inhibits osteoclast formation and function by suppressing RANKL-induced activation of the p38/JNK-cFos/NFATc1 signaling cascade, thereby preventing ovariectomy-induced osteoporosis in mice. Thus, PLM can potentially be used as an anti-resorption drug or dietary supplement for the prevention of PMOP.

Persistent left superior vena cava isolation in patients with atrial fibrillation: Selective or empirical?

BACKGROUND: Persistent left superior vena cava (PLSVC) is the most prevalent form of thoracic venous abnormality and can serve as a significant arrhythmogenic source in atrial fibrillation (AF). METHODS AND RESULTS: Among the 3950 patients who underwent radiofrequency ablation for AF between September 2014 to April 2020, 17 patients (mean age 59.4 ± 8.0 years, 64.7% male) with PLSVC were identified. Among them, nine patients (52.9%) had a prior history of pulmonary vein isolation (PVI) alone. Eight out of nine patients who experienced AF recurrence underwent PLSVC isolation with or without pulmonary vein (PV) reconnection. For the remaining eight patients (47.1%), PVI plus PLSVC isolation were performed during the index procedure. Ectopy originating from PLSVC was documented in 11 patients (64.7%) and successful PLSVC isolation was achieved in 16 patients (94.1%). After a median follow-up of 28.3 months, freedom from AF/ atrial tachycardia (AT) was observed in 13 patients (76.5%). CONCLUSION: Empirical PLSVC isolation beyond PVI appears to be a feasible and safe strategy to prevent AF recurrence in patients with concomitant PLSVC.

Gaucher disease in a patient with membranoproliferative glomerulonephritis: case report.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive inherited, lysosomal storage disoder that involves liver, spleen, lung, bone, bone marrow even central nervous. However, GD associated membranoproliferative glomerulonephritis (MPGN) is seldom reported. CASE PRESENTATION: Here we described a case of 35-year-old man suffering from GD with hepatosplenomegaly, ascites, bone destruction, myelofibrosis and MPGN. Renal biopsy revealed MPGN and Gaucher cells presented in the glomeruli capillaries. ß-glucosidase activity was 1.95nmol/1 h/mg and gene detection demonstrated that one homozygous pathogenic variant Leu483Pro in GBA. He received the treatment of oral prednisone and mycophenolate mofetil and his ascites and renal outcomes had been significantly improved. CONCLUSIONS: Therapy of prednisone and mycophenolate mofetil may be an optional choice for patients with Gaucher disease who have no opportunity to use enzyme treatment.

Electroacupuncture-Modulated MiR-106b-5p Expression Enhances Autophagy by Targeting Beclin-1 to Promote Motor Function Recovery After Spinal Cord Injury in Rats.

OBJECTIVE: Electroacupuncture (EA) has a definite effect on the treatment of spinal cord injuries (SCIs), but its underlying molecular mechanism remains unclear. Meanwhile, MiR106b-5p is an autophagy- and apoptosis-related microribonucleic acid, but whether it regulates the progression of autophagy and apoptosis in SCIs is yet undetermined. As such, this study aimed to elucidate the involvement of miR-106b-5p in the EA treatment of an SCI. METHODS: The miR-106b-5p level was detected by quantitative real-time polymerase chain reaction. In vitro, SH-SY5Y cells were transfected with miR-106b-5p mimics or inhibitors to regulate the miR-106b-5p expression, while in vivo, SCI rats were treated with EA for 7 days at the bilateral Zusanli (ST36) and Jiaji (EX-B2) acupoints. The motor function was evaluated using the Basso-Beattie-Bresnahan (BBB) criteria. Further, autophagic vacuoles, pathological damage, and neuronal cell morphology were observed by transmission electron microscopy, as well as by hematoxylin and eosin and Nissl staining, respectively. RESULTS: The miR-106b-5p level, which can interact directly with Beclin-1 by influencing its expression, as well as the expressions of P62, Caspase-3, and Bax, was upregulated after an SCI, but it decreased after EA. Moreover, the ratio of LC3-II to LC3-I was upregulated after EA. EA can enhance autophagy, reduce neuronal apoptosis, and minimize motor dysfunction and histopathological deficits after an SCI. More importantly, however, all the above effects induced by EA can be reversed after an injection of miR-106-5p agomir to produce an overexpression of miR-106b-5p. CONCLUSION: EA treatment could downregulate miR-106b-5p to alleviate SCI-mediated injuries by promoting autophagy and inhibiting apoptosis.

Pharmacological inhibition of protein S-palmitoylation suppresses osteoclastogenesis and ameliorates ovariectomy-induced bone loss.

Background: Excessive osteoclast formation disrupts bone homeostasis, thereby significantly contributing to pathological bone loss associated with a variety of diseases. Protein S-palmitoylation is a reversible post-translational lipid modification catalyzed by ZDHHC family of palmitoyl acyltransferases, which plays an important role in various physiological and pathological processes. However, the role of palmitoylation in osteoclastogenesis has never been explored. Consequently, it is unclear whether this process can be targeted to treat osteolytic bone diseases that are mainly caused by excessive osteoclast formation. Materials and methods: In this study, we employed acyl-biotin exchange (ABE) assay to reveal protein S-palmitoylation in differentiating osteoclasts (OCs). We utilized 2-bromopalmitic acid (2-BP), a pharmacological inhibitor of protein S-palmitoylation, to inhibit protein palmitoylation in mouse bone marrow-derived macrophages (BMMs), and tested its effect on receptor activator of nuclear factor κß ligand (RANKL)-induced osteoclast differentiation and activity by TRAP staining, phalloidin staining, qPCR analyses, and pit formation assays. We also evaluated the protective effect of 2-BP against estrogen deficiency-induced bone loss and bone resorption in ovariectomized (OVX) mice using µCT, H&E staining, TRAP staining, and ELISA assay. Furthermore, we performed western blot analyses to explore the molecular mechanism underlying the inhibitory effect of 2-BP on osteoclastogenesis. Results: We found that many proteins were palmitoylated in differentiating OCs and that pharmacological inhibition of palmitoylation impeded RANKL-induced osteoclastogenesis, osteoclast-specific gene expression, F-actin ring formation and osteoclastic bone resorption in vitro, and to a lesser extent, osteoblast formation from MC3T3-E1 cells. Furthermore, we demonstrated that administration of 2-BP protected mice from ovariectomy-induced osteoporosis and bone resorption in vivo. Mechanistically, we showed that 2-BP treatment inhibited osteoclastogenesis partly by downregulating the expression of c-Fos and NFATc1 without overtly affecting RANKL-induced activation of osteoclastogenic AKT, MAPK, and NF-κB pathways. Conclusion: Pharmacological inhibition of palmitoylation potently suppresses RANKL-mediated osteoclast differentiation in vitro and protects mice against OVX-induced osteoporosis in vivo. Mechanistically, palmitoylation regulates osteoclast differentiation partly by promoting the expression of c-Fos and NFATc1. Thus, palmitoylation plays a key role in promoting osteoclast differentiation and activity, and could serve as a potential therapeutic target for the treatment of osteoporosis and other osteoclast-related diseases. The translational potential of this article: The translation potential of this article is that we first revealed palmitoylation as a key mechanism regulating osteoclast differentiation, and therefore provided a potential therapeutic target for treating osteolytic bone diseases.

Crosstalk between ferroptosis and steroid hormone signaling in gynecologic cancers.

Ferroptosis is a novel types of regulated cell death and is widely studied in cancers and many other diseases in recent years. It is characterized by iron accumulation and intense lipid peroxidation that ultimately inducing oxidative damage. So far, signaling pathways related to ferroptosis are involved in all aspects of determining cell fate, including oxidative phosphorylation, metal-ion transport, energy metabolism and cholesterol synthesis progress, et al. Recently, accumulated studies have demonstrated that ferroptosis is associated with gynecological oncology related to steroid hormone signaling. This review trends to summarize the mechanisms and applications of ferroptosis in cancers related to estrogen and progesterone, which is expected to provide a theoretical basis for the prevention and treatment of gynecologic cancers.

Scar-related atrial macroreentries: Different arrhymogenic basis generates different reentry type.

BACKGROUND: Catheter ablation is an established therapeutic strategy to treat scar-related macroreentry atrial tachycardia (MAT). However, the scar properties and arrhythmogenicity and the reentry type have not been clearly defined. METHODS AND RESULTS: A total of 122 patients with scar-related MAT were enrolled in this study. The atrial scars were classified into two categories: spontaneous scars (Group A: n = 28) and iatrogenic scars (Group B: n = 94). According to the relationship between scar location and the reentry circuit, MAT was described as scar pro-flutter MAT, scar-dependent MAT, and scar-mediated MAT. The reentry type of MAT was significantly different between Groups A and B: pro-flutter (40.5% vs. 62.0%, p = 0.02), scar-dependent AT (40.5% vs. 13.0%, p < 0.001), and scar-mediated AT (19.0% vs. 25.0%, p = 0.42). After a median follow-up of 25 months, 21 patients with AT recurrence were observed. Compared with the spontaneous group, there was a lower recurrence rate of MAT in the iatrogenic group (28.6% vs. 10.6%, p = 0.03). CONCLUSION: Scar-related MAT has three reentry types, and the proportion of each type varies with the scar properties and its arrhythmogenic basis. Optimization of the ablation strategy based on the scar properties to improve the long-term outcome of catheter ablation of MAT is necessary.

Moderate mechanical stimulation antagonizes inflammation of annulus fibrosus cells through YAP-mediated suppression of NF-κB signaling.

Intervertebral disc degeneration (IDD) is a leading cause of low back pain. The inflammatory responses caused by aberrant mechanical loading are one of the major factors leading to annulus fibrosus (AF) degeneration and IDD. Previous studies have suggested that moderate cyclic tensile strain (CTS) can regulate anti-inflammatory activities of AF cells (AFCs), and Yes-associated protein (YAP) as a mechanosensitive coactivator senses diverse types of biomechanical stimuli and translates them into biochemical signals controlling cell behaviors. However, it remains poorly understood whether and how YAP mediates the effect of mechanical stimuli on AFCs. In this study, we aimed to investigate the exact effects of different CTS on AFCs as well as the role of YAP signaling involving in it. Our results found that 5% CTS inhibited the inflammatory response and promoted cell growth through inhibiting the phosphorylation of YAP and nuclear localization of NF-κB, while 12% CTS had a significant proinflammatory effect with the inactivation of YAP activity and the activation of NF-κB signaling in AFCs. Furthermore, moderate mechanical stimulation may alleviate the inflammatory reaction of intervertebral discs through YAP-mediated suppression of NF-κB signaling in vivo. Therefore, moderate mechanical stimulation may serve as a promising therapeutic approach for the prevention and treatment of IDD.

An evaluation of the clinical efficacy of the application of 28mm cryoballoon for linear ablation of left atrial apex combined with enlarged pulmonary vein vestibule ablation for persistent atrial fibrillation.

OBJECTIVE: to retrospectively investigate the efficacy and safety of the application of 28 mm cryoballoon for pulmonary vein electrical isolation (PVI) combined with top left atrial linear ablation and pulmonary vein vestibular expansion ablation for persistent atrial fibrillation. METHODS: From July 2016 to December 2020, 413 patients diagnosed with persistent atrial fibrillation were evaluated, including 230 (55.7%) in the PVI group (PVI only) and 183 (44.3%) in the PVIPLUS group (PVI plus ablation of the left atrial apex and pulmonary vein vestibule). The safety and efficacy of the two groups were retrospectively analyzed. RESULTS: The AF/AT/AFL-free survival rates at 6, 12, 18, 24 and 30 months after procedure was 86.6%, 72.6%, 70.0%, 61.1% and 56.3% in the PVI group and 94.5%, 87.0%, 84.1%, 75.0% and 67.9% in the PVIPLUS group, respectively. At 30 months after procedure, the AF/AT/AFL-free survival rate was significantly higher in the PVIPLUS group than in the PVI group (P = 0.036; HR:0.63; 95% CI:0.42 to 0.95). CONCLUSION: The application of 28-mm cryoballoon for pulmonary vein electrical isolation combined with linear ablation of the left atrial apex and expanded ablation of the pulmonary vein vestibule improves the outcome of persistent atrial fibrillation.

Upregulation of ß-catenin signaling represents a single common pathway leading to the various phenotypes of spinal degeneration and pain.

Spine degeneration is an aging-related disease, but its molecular mechanisms remain unknown, although elevated ß-catenin signaling has been reported to be involved in intervertebral disc degeneration. Here, we determined the role of ß-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit (FSU), which includes the intervertebral disc, vertebra and facet joint and is the smallest physiological motion unit of the spine. We showed that pain sensitivity in patients with spinal degeneration is highly correlated with ß-catenin protein levels. We then generated a mouse model of spinal degeneration by transgenic expression of constitutively active ß-catenin in Col2+ cells. We found that ß-catenin-TCF7 activated the transcription of CCL2, a known critical factor in osteoarthritic pain. Using a lumbar spine instability model, we showed that a ß-catenin inhibitor relieved low back pain. Our study indicates that ß-catenin plays a critical role in maintaining spine tissue homeostasis, its abnormal upregulation leads to severe spinal degeneration, and its targeting could be an avenue to treat this condition.

Targeting Endogenous Reactive Oxygen Species Removal and Regulating Regenerative Microenvironment at Annulus Fibrosus Defects Promote Tissue Repair.

The excessive reactive oxygen species (ROS) level, inflammation, and weak tissue regeneration ability after annulus fibrosus (AF) injury constitute an unfavorable microenvironment for AF repair. AF integrity is crucial for preventing disc herniation after discectomy; however, there is no effective way to repair the AF. Herein, a composite hydrogel integrating properties of antioxidant, anti-inflammation, and recruitment of AF cells is developed through adding mesoporous silica nanoparticles modified by ceria and transforming growth factor ß3 (TGF-ß3) to the hydrogels. The nanoparticle loaded gelatin methacrylate/hyaluronic acid methacrylate composite hydrogels eliminate ROS and induce anti-inflammatory M2 type macrophage polarization. The released TGF-ß3 not only plays a role in recruiting AF cells but is also responsible for promoting extracellular matrix secretion. The composite hydrogels can be solidified in situ in the defect area to effectively repair AF in rats. The strategies targeting endogenous ROS removal and improving the regenerative microenvironment by the nanoparticle-loaded composite hydrogels have potential applications in AF repair and intervertebral disc herniation prevention.

Use of a 3D-printed body surface percutaneous puncture guide plate in vertebroplasty for osteoporotic vertebral compression fractures.

BACKGROUND: Percutaneous vertebroplasty (PVP) has been used widely to treat osteoporotic vertebral compression fractures (OVCFs). However, it has many disadvantages, such as excessive radiation exposure, long operation times, and high cement leakage rates. This study was conducted to explore the clinical effects and safety of the use of a three-dimensional (3D)-printed body-surface guide plate to aid PVP for the treatment of OVCFs. METHODS: This prospective cohort study was conducted with patients with OVCFs presenting between October 2020 and June 2021. Fifty patients underwent traditional PVP (group T) and 47 patients underwent PVP aided by 3D-printed body-surface guide plates (3D group). The following clinical and adverse events were compared between groups: the puncture positioning, puncture, fluoroscopy exposure and total operation times; changes in vertebral height and the Cobb angle after surgery relative to baseline; preoperative and postoperative visual analog scale and Oswestry disability index scores; and perioperative complications (bone cement leakage, neurological impairment, vertebral infection, and cardiopulmonary complications. RESULTS: The puncture, adjustment, fluoroscopy, and total operation times were shorter in the 3D group than in group T. Visual analog scale and Oswestry disability index scores improved significantly after surgery, with significant differences between groups (both p < 0.05). At the last follow-up examination, the vertebral midline height and Cobb angle did not differ between groups. The incidence of complications was significantly lower in the 3D group than in group T (p < 0.05). CONCLUSION: The use of 3D-printed body-surface guide plates can simplify and optimize PVP, shortening the operative time, improving the success rate, reducing surgical complications, and overall improving the safety of PVP.

Systematic Review and Meta-Analysis of the Evaluation of the Efficacy of Manipulation and Cervical Traction in the Treatment of Radical Cervical Spondylosis.

Background: With the accelerated pace of life in modern society, changes in work style, and the popularity of computers, the prevalence of cervical spondylosis (CSR) is increasing, and the age of onset is advancing. Once suffering from this disease, it is often difficult to cure and recurring, with complex clinical symptoms, causing a serious impact on human health. Objective: To evaluate the efficacy of manipulation and cervical traction in the treatment of radical cervical spondylosis. Methods: The PubMed, CNKI, and Wanfang databases were searched for literature. The literature related to this study was included according to selective criteria and inhibitory elimination criteria, and valuable information was selected for statistical analysis, resulting in a total of 11 randomized controlled trials with 994 subjects. Results: The short-term efficacy of manual treatment for CSR was superior to that of cervical traction alone (P < 0.05); subgroup analysis showed that the short-term efficacy of pulling or rotational manipulation was superior to that of cervical traction (P < 0.05). The mean difference between symptoms and manipulation VAS scores was higher before and after treatment when compared with cervical traction for CSR (P < 0.05); the subgroup analysis showed that VAS scores, upper extremity anesthesia scores, and survivorship scores were lower for pulling or rotating manipulation than for cervical traction (P < 0.05). Conclusion: The advantages of manual therapy in terms of short-term efficacy, VAS pain scores, neck pain, upper extremity anesthesia, and survivorship improvement provide a theoretical basis for its clinical impact.

Efficacy of extended antrum ablation based on substrate mapping plus pulmonary vein isolation in the treatment of atrial fibrillation.

INTRODUCTION AND OBJECTIVES: Pulmonary vein isolation (PVI) technique has become the cornerstone of atrial fibrillation (AF) catheter ablation. The objective of this study was to assess the efficacy and safety of extended antrum ablation based on electrophysiological substrate mapping plus PVI in AF patients who underwent cryoballoon ablation. METHODS: In this observational study, a total of 121 paroxysmal AF patients and 80 persistent AF patients who did not achieve the procedure endpoint after cryoballoon ablation received extra extended antrum ablation (EAA) based on electrophysiological substrate mapping via radiofrequency ablation (EAA group). As a control group (PVI group), among paroxysmal AF and persistent AF patients, we conducted a propensity score-matched cohort, in whom only PVI was completed. RESULTS: The average follow-up time was 15.27±7.34 months. Compared with PVI group, paroxysmal AF patients in the EAA group had a significantly higher rate of AF-free survival (90.1% vs. 80.2%, p=0.027) and AF, atrial flutter, or atrial tachycardia (AFLAT) -free rate survival (89.3% vs. 79.3%, p=0.031). Persistent AF patients in the EAA group also had a significantly higher rate of AF-free survival (90.0% vs. 75.0%, p=0.016) and AFLAT-free survival (88.8% vs. 75.0%, p=0.029) than PVI group. Complication rates did not significantly differ between both groups, in either paroxysmal AF or persistent AF patients. CONCLUSION: Our findings demonstrate that extra extended antrum ablation based on electrophysiological substrate mapping is effective and safe. Moreover, the strategy can improve the outcome of AF cryoablation.

School-Based Comprehensive Strength Training Interventions to Improve Muscular Fitness and Perceived Physical Competence in Chinese Male Adolescents.

Purpose: This research was to see how effective and feasible school-based comprehensive strength training programs are in improving muscular fitness and perceived physical competence in Chinese male adolescents. Methods: A total of 123 participants (13.46 ± 0.60 years) were randomized to comprehensive strength training intervention group (CST) (n = 62) and the control group (CON) (n = 61). The training sessions were performed three times a week for ten weeks in CST. Muscular fitness (i.e., muscular strength, power, and muscular endurance) and perceived physical competence were assessed at initial testing and final testing. Results: The subjects in the CST significantly improved their mean performance in standing long jump (p < 0.05), vertical jump (p < 0.05), 1 min push-ups (p < 0.05), 1 min sit-ups (p < 0.05), handgrip strength (p < 0.05), and perceived physical competence (p < 0.05) after the intervention. Moreover, the CST were greater in standing long jump (p < 0.05), vertical jump (p < 0.05), 1 min sit-ups (p < 0.05), handgrip strength (p < 0.05), and perceived physical competence (p < 0.05) compared to the CON, but no in 1 min push-ups (p > 0.05). Conclusions: The comprehensive strength training interventions designed in this study can significantly increase male adolescents' muscular fitness, especially in the lower extremity muscle power and abdominal core endurance, and can enhance their perceived physical competence.

Suppressor of fused-restrained Hedgehog signaling in chondrocytes is critical for epiphyseal growth plate maintenance and limb elongation in juvenile mice.

Hedgehog (Hh) signaling plays multiple critical roles in regulating chondrocyte proliferation and differentiation during epiphyseal cartilage development. However, it is still unclear whether Hh signaling in chondrocytes is required for growth plate maintenance during juvenile growth, and whether sustained activation of Hh signaling in chondrocytes promotes limb elongation. In this study, we first utilized Hh reporter mice to reveal that Hh signaling was activated in resting and columnar chondrocytes in growth plates of juvenile and adult mice. Next, we genetically modulated Hh signaling by conditionally deleting Smo or Sufu in all or a subpopulation of growth plate chondrocytes, and found that ablation of either Smo or Sufu in chondrocytes of juvenile mice caused premature closure of growth plates and shorter limbs, whereas Osx-Cre-mediated deletion of either of these two genes in prehypertrophic chondrocytes did not lead to obvious growth plate defects, indicating that Hh signaling mainly functions in resting and/or columnar chondrocytes to maintain growth plates at the juvenile stage. At the cellular level, we found that chondrocyte-specific ablation of Smo or Sufu accelerated or suppressed chondrocyte hypertrophy, respectively, whereas both decreased chondrocyte proliferation and survival. Thus, our study provided the first genetic evidence to establish the essential cell-autonomous roles for tightly-regulated Hh signaling in epiphyseal growth plate maintenance and limb elongation during juvenile growth.

Acid-Directed Electrostatic Self-Assembly Generates Charge-Reversible Bacteria for Enhanced Tumor Targeting and Low Tissue Trapping.

Despite recent preclinical progress with oncolytic bacteria in cancer therapy, dose-limiting toxicity has been a long-standing challenge for clinical application. Genetic and chemical modifications for enhancing the bacterial tumor-targeting ability have been unable to establish a balance between increasing its specificity and effectiveness while decreasing side effects. Herein, we report a simple, highly efficient method for rapidly self-assembling a clinically used lipid on bacterium and for reducing its minimum effective dose and toxicity to normal organs. The resultant bacteria present the ability to reverse-charge between neutral and acidic solutions, thus enabling weak interactions with the negatively charged normal cells, hence increasing their biocompatibility with blood cells and with the immune system. Additionally, the lipid-coated bacteria exhibit a longer blood circulation lifetime and low tissue trapping compared with the wild-type strains. Thereby, the engineered bacteria show enhanced tumor specificity and effectiveness even at low doses. Multiple visualization techniques are used for vividly demonstrating the time course of bacterial circulation in the blood and normal organs after intravenous administration. We believe that these methods for biointerfacial lipid self-assembly and evaluation of bacterial systemic circulation possess vast potential in exquisitely fabricating engineered bacteria for cancer therapy in the future.

Prevalence and Risk Factors for Fall among Rural Elderly: A County-Based Cross-Sectional Survey.

Aim: The aim of the study was to provide evidence for the prevention and reduction of falls in the elderly living in rural areas by analyzing epidemiological data of falls among the rural older people (>65 years old) and identifying the risk and protective factors. Methods: This study analyzed the sociodemographic characteristics, living environment, lifestyle, chronic disease condition, mental health, activities of daily living (ADL), and detailed information of falls of 3752 rural elderly. Rank tests, chi-square tests, and binary logistic regression were used for data analysis. Results: The prevalence of falls was 30.0%, and the 75-84-years age group had the highest fall rate (18.8%). According to the binary logistic regression analysis, six variables, including roughage intake frequency, age, gender, cane use, floor tiles, and IADL, were involved in the fall patterns. Low roughage intake (OR = 2.48, 95% CI 1.24-4.97), female gender (OR = 2.12, 95% CI 1.48-3.05), the use of a cane (OR = 2.11, 95% CI 1.08-4.10), and medium IADL (OR = 2.02, 95% CI 1.89-2.32) were the top four risk factors. Conclusion: The fall in the rural elderly was mainly due to the poor living and working conditions. Routine fall assessment could address several preventable risk factors to reduce the prevalence and mitigate the harm of falls.