Biomimetic Nanovehicle-Enabled Targeted Depletion of Intratumoral Fusobacterium nucleatum Synergizes with PD-L1 Blockade against Breast Cancer.

Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.

Efficacy of Internet-Based Cognitive Behavioral Therapy for Subthreshold Depression Among Older Adults in Institutional Long-Term Care Settings: Pragmatic Randomized Controlled Trial.

BACKGROUND: Subthreshold depression (sD) is prevalent in older populations in long-term care (LTC) settings, but psychological therapy in LTC settings in China is not readily available. Thus, internet-based cognitive behavioral therapy (ICBT) may be suitable for this population, but research on the efficacy of ICBT for older adults with sD, especially those living in LTC settings, is limited. OBJECTIVE: This study aimed to evaluate the efficacy and acceptability of ICBT treatment for sD among LTC residents in China. We also examined whether ICBT is as effective as group-based cognitive behavioral therapy (CBT) for treating sD in this population. METHODS: We conducted a pragmatic randomized controlled trial, which included 18 LTC institutions. A total of 354 participants were randomized to ICBT, group-based CBT, or a waiting list and were followed up for 12 months. The primary outcome was self-reported depressive symptoms on the Center for Epidemiological Studies Depression Scale (CES-D). Secondary outcomes were the scores of the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-Item (GAD-7), and Geriatric Depression Scale (GDS). A mixed-effects model was used to assess the efficacy of ICBT. RESULTS: The ICBT group showed a significant improvement in self-reported depressive symptoms, which was maintained at the 12-month follow-up (all P<.001). The ICBT group exhibited a significantly larger reduction in the scores of the CES-D (Cohen d=0.07, 95% CI 0.04-0.09; P=.01), PHQ-9 (d=0.30, 95% CI 0.28-0.33; P<.001), GDS (d=0.10, 95% CI 0.08-0.13; P<.001), and GAD-7 (d=0.19, 95% CI 0.17-0.22; P<.001) compared with a waiting list at postintervention. ICBT had significantly stronger effects than CBT on the PHQ-9 and GAD-7 at postintervention (d=0.15, 95% CI 0.13-0.17; P<.001 and d=0.21, 95% CI 0.19-0.23; P<.001, respectively), 6-month follow-up (d=0.18, 95% CI 0.16-0.21; P<.001 and d=0.18, 95% CI 0.15-0.21; P<.001, respectively), and 12-month follow-up (d=0.15, 95% CI 0.11-0.19; P<.001 and d=0.18, 95% CI 0.14-0.21; P<.001, respectively). CONCLUSIONS: ICBT is a relatively effective and acceptable intervention for reducing depressive symptoms among Chinese LTC residents with sD. These findings indicate the usefulness of ICBT application for sD in LTC settings. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000030697; https://www.chictr.org.cn/showproj.aspx?proj=50781.

DP7-C/mir-26a system promotes bone regeneration by remodeling the osteogenic immune microenvironment.

OBJECTIVE: This study investigates the DP7-C/miR-26a complex as a stable entity resulting from the combination of miR-26a with the immunomodulatory peptide DP7-C. Our focus is on utilizing DP7-C loaded with miR-26a to modulate the immune microenvironment in bone and facilitate osteogenesis. METHODS: The DP7-C/miR-26a complex was characterized through transmission electron microscopy, agarose electrophoresis, and nanoparticle size potentiometer analysis. Transfection efficiency and cytotoxicity of DP7-C were assessed using flow cytometry and the CCK-8 assay. We validated the effects of DP7-C/miR-26a on bone marrow mesenchymal stem cells (BMSCs) and macrophages RAW 264.7 through gene expression and protein synthesis assays. A comprehensive evaluation of appositional bone formation involved micro-CT imaging, histologic analysis, and immunohistochemical staining. RESULTS: DP7-C/miR-26a, a nanoscale, and low-toxic cationic complex, demonstrated the ability to enter BMSCs and RAW 264.7 via distinct pathways. The treatment with DP7-C/miR-26a significantly increased the synthesis of multiple osteogenesis-related factors in BMSCs, facilitating calcium nodule formation in vitro. Furthermore, DP7-C/miR-26a promoted M1 macrophage polarization toward M2 while suppressing the release of inflammatory factors. Coculture studies corroborated these findings, indicating significant repair of rat skull defects following treatment with DP7-C/miR-26a. CONCLUSION: The DP7-C/miR-26a system offers a safer, more efficient, and feasible technical means for treating bone defects.

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.

Dietary protein in early pregnancy and gestational diabetes mellitus: a prospective cohort study.

PURPOSE: The relationship between dietary protein intake and the risk of gestational diabetes mellitus (GDM) remains inconsistent and unclear. Here, we examined the correlation between the various sources of protein intake among Chinese pregnant women and GDM. METHODS: This prospective cohort study included 1060 pregnant women at 6-13+6 weeks of gestation from Guangdong Provincial Hospital for Women and Children, South China. The participants' intake of dietary protein was assessed using a validated quantitative food frequency questionnaire during the early trimester. GDM was diagnosed via an oral glucose tolerance test performed at 24-28 gestational weeks. Logistic regression analysis was used to evaluate the association between dietary protein intake during pregnancy and GDM. Furthermore, we applied restricted cubic splines to determine their linear relationship. RESULTS: About 26.3% (n = 279) of pregnant women were diagnosed with GDM. Animal protein intake was revealed to have a positive correlation with GDM risk (Q4 vs. Q1: OR, 2.78; 95% CI, 1.46-5.34; P = 0.015), whereas high intake levels of dietary plant protein were linked to reduced GDM risk (Q4 vs. Q1: OR, 0.43; 95% CI, 0.25-0.73). In stratified analysis, the relationship between protein and GDM was stronger during early pregnancy in women with obesity. However, total protein intake did not show a significant association with GDM. CONCLUSIONS: Our study findings suggest that a plant protein-based diet was associated with reduced GDM risk, whereas the dietary intake of animal protein was positively associated with GDM risk among Chinese women during early pregnancy.

Internet-Based Self-Help Mindful Self-Compassion Intervention for Parents of Children With Cancer: A Pilot Study.

BACKGROUND: Parents of children with cancer may experience persistent psychological distress and impaired physical health throughout their children's diagnosis and treatment. OBJECTIVE: This study aimed to develop a mindful self-compassion program for parents of children with cancer and explore its effect. METHODS: This pre-post-test study without a control group was conducted with 34 Chinese parents of children with cancer, using mixed methods. Participants received a 6-week internet-based self-help mindful self-compassion intervention. Self-compassion, post-traumatic stress symptoms, depression, and sleep quality were measured at baseline and at 10 weeks post-baseline. Semi-structured interviews were conducted with 9 completers within 10 days after the intervention was completed. RESULTS: Significant differences were observed in self-compassion, re-experiencing, physical depressive symptoms, and sleep quality. Two participants reported feeling miserable or recalling distressing experiences, of which one withdrew from the study while the other completed the intervention. CONCLUSION: The program could improve self-compassion, re-experiencing, physical depressive symptoms, and sleep quality in parents of children with cancer, which demonstrated the feasibility of delivering a self-help mindful self-compassion intervention through the internet. Increasing retention rates in future studies merits further discussion.

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.

Impact of the COVID-19 Pandemic on the Management of Juvenile Idiopathic Arthritis: Analysis of United States Commercial Insurance Data.

BACKGROUND/OBJECTIVE: Given limited information on health care and treatment utilization for juvenile idiopathic arthritis (JIA) during the pandemic, we studied JIA-related health care and treatment utilization in a commercially insured retrospective US cohort. METHODS: We studied rates of outpatient visits, new disease-modifying antirheumatic drug (DMARD) initiations, intra-articular glucocorticoid injections (iaGC), dispensed oral glucocorticoids and opioids, DMARD adherence, and DMARD discontinuation by quarter in March 2018-February 2021 (Q1 started in March). Incident rate ratios (IRR, pandemic vs prepandemic) with 95% confidence intervals (CIs) were estimated using multivariable Poisson or Quasi-Poisson models stratified by diagnosis recency (incident JIA, <12 months ago; prevalent JIA, ≥12 months ago). RESULTS: Among 1294 children diagnosed with JIA, total and in-person outpatient visits for JIA declined during the pandemic (IRR, 0.88-0.90), most markedly in Q1 2020. Telemedicine visits, while higher during the pandemic, declined from 21% (Q1) to 13% (Q4) in 2020 to 2021. During the pandemic, children with prevalent JIA, but not incident JIA, had lower usage of iaGC (IRR, 0.60; 95% CI, 0.34-1.07), oral glucocorticoids (IRR, 0.47; 95% CI, 0.33-0.67), and opioids (IRR, 0.44; 95% CI, 0.26-0.75). Adherence to and discontinuation of DMARDs was similar before and during the pandemic. CONCLUSIONS: In the first year of the pandemic, visits for JIA dropped by 10% to 12% in commercially insured children in the United States, declines partly mitigated by use of telemedicine. Pandemic-related declines in intra-articular glucocorticoids, oral glucocorticoids, and opioids were observed for children with prevalent, but not incident, JIA. These changes may have important implications for disease control and quality of life.

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.

Effects of combining immune checkpoint inhibitors and anti-angiogenic agents on bone metastasis in non-small cell lung cancer patients.

This study aimed to evaluate the efficacy of combining immune checkpoint inhibitors (ICIs) and anti-angiogenic agents in treating lung cancer patients with bone metastases (BMs), as it is unclear whether this combination is effective for this condition. Non-small cell lung cancer patients with BMs receiving ICIs were divided into experimental and control groups based on anti-angiogenic treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method, with log-rank test for comparisons. Prognostic factors were determined by univariate and multivariate Cox regression analyses. The study included 95 patients. The experimental group (n = 42) had a higher disease control rate (DCR) (90.5% vs. 68.6%, p = .009), objective response rate (ORR) (35.7% vs. 24.5%, p = .235), and longer median bone PFS (14.3 months vs. 8.3 months, p = .011) for bone metastasis. However, there were no significant differences in overall DCR (92.8% vs. 86.7%, p = .339), ORR (64.3% vs. 62.3%, p = .839), and PFS (12.4 months vs. 11.6 months, p = 0.383) between the 2 groups. The experimental group had a lower incidence of skeleton-related events (SREs) (28.6% vs. 35.8%, p = .425), and SRE patients had shorter PFS (7.7 vs. 14.3 months, p < .001) and OS (12.1 vs. 19.0 months, p = .028). Anti-angiogenic therapy (HR = 0.55, p = .012) and SRE (HR = 2.93, p < .001) were identified as independent prognostic factors for bone metastatic PFS. Adverse events were slightly higher in the experimental group (29.3% vs. 18.9%, p = .238), but not statistically significant. The combination of ICIs and anti-angiogenic agents leads to a significant PFS for BMs and potentially decreases SRE.

Effect of cooking methods on metabolites of deep purple-fleshed sweetpotato.

The effects of different cooking methods on purple-fleshed sweetpotato (PFSP) metabolites were systematically explored, containing the changes of starch, soluble sugar, volatile organic compounds and non-target metabolites after steaming, boiling and baking. Compared to raw samples, the steamed samples showed the greatest changes in starch (degraded from 53.01% to 39.5%) and soluble sugar content (increased from 11.82% to 29.08%), while the baked samples showed insignificant changes in starch (51.06%). In total, 64 volatile organic compounds were identified in PFSP, with aldehydes decreasing and terpenes increasing after cooking. However, most of them were low in content and contributed weak aroma for PFSP. More importantly, 871 non-volatile metabolites were detected in PFSP, and 83.5% of which were well-preserved after cooking, while most of the changes were concentrated in phenylpropanoids, amino acids and carbohydrates. This study enriches the understanding of quality changes after PFSP cooking and helps consumers choose the right cooking method.

Genetic fingerprint construction and genetic diversity analysis of sweet potato (Ipomoea batatas) germplasm resources.

BACKGROUND: China is the largest producer of sweet potato in the world, accounting for 57.0% of the global output. Germplasm resources are the basis for promoting innovations in the seed industry and ensuring food security. Individual and accurate identification of sweet potato germplasm is an important part of conservation and efficient utilization. RESULTS: In this study, nine pairs of simple sequence repeat molecular markers and 16 morphological markers were used to construct genetic fingerprints for sweet potato individual identification. Combined with basic information, typical phenotypic photographs, genotype peak graphs, and a two-dimensional code for detection and identification were generated. Finally, a genetic fingerprint database containing 1021 sweet potato germplasm resources in the "National Germplasm Guangzhou Sweet Potato Nursery Genebank in China" was constructed. Genetic diversity analysis of the 1021 sweet potato genotypes using the nine pairs of simple sequence repeat markers revealed a narrow genetic variation range of Chinese native sweet potato germplasm resources, and Chinese germplasm was close to that from Japan and the United States, far from that from the Philippines and Thailand, and the furthest from that from Peru. Sweet potato germplasm resources from Peru had the richest genetic diversity, supporting the view that Peru is the center of origin and domestication of sweet potato varieties. CONCLUSIONS: Overall, this study provides scientific guidance for the conservation, identification, and utilization of sweet potato germplasm resources and offers a reference to facilitate the discovery of important genes to boost sweet potato breeding.

Regulation of stability and density of energetic materials via isomerism.

Selective regulation of stability and density via isomerism is a promising strategy for developing energetic materials. In this work, we selectively introduced dinitromethyl groups at different positions of 4-nitro-1,2,3-triazole. The regional heterogeneity endows a high crystal density by virtue of the dense packing; on the other hand, it changes the charge distribution in the molecule, and reinforces the hydrogen bonding interactions, all of which stabilize the material. The resulting compounds exhibit excellent detonation properties and impact sensitivity that are comparable to those of HMX (Dv = 9250 m s-1 and IS = 10 J).

Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States.

BACKGROUND: In the United States, major depressive disorder (MDD) is one of the most prevalent mental health disorders. Treatment guidelines for MDD recommend pharmacologic and nonpharmacologic therapies tailored to the patient's disease severity, level of function, and comorbid health conditions. While previous studies examined real-world pharmacologic treatment patterns and costs among patients with MDD, few have examined the use of nonpharmacologic treatments and their association with health care resource utilization (HCRU) and cost. OBJECTIVE: To describe prevalence and associations between patient/provider characteristics and treatment modality and characterize HCRU and cost by treatment modality for patients with newly diagnosed MDD. METHODS: Commercially insured US patients, aged 18-62 years with newly diagnosed MDD between January 1, 2017, and September 30, 2019, were retrospectively identified from the Healthcare Integrated Research Database. Eligible patients were continuously enrolled in the health plan for 1 year before and 2 years after the first MDD diagnosis (index date). Those with co-occurring schizophrenia, bipolar disorder, postpartum depression, substance use disorder, and any prior MDD treatments were excluded. Treatment modalities assessed in the 2-year post-index period included antidepressant only (Rx-only), nonpharmacologic only (non-Rx-only), both antidepressant and nonpharmacologic (combination), and no treatment. HCRU and costs were assessed in the 2-year post-index period by treatment modality. Regression models identified associations between patient/provider characteristics and treatment modality, and the relationship between treatment modality and MDD severity changes. RESULTS: In total, 12,657 patients were included (mean age: 36 years; 60% female). During follow-up, 34% of patients received Rx-only, 25% received non-Rx-only, 28% received combination, and 13% received no treatment. MDD severity at diagnosis (26% mild, 54% moderate, 20% severe) was available for 51% of patients. Post-index inpatient hospitalizations were 11% for those with Rx-only, 10% for non-Rx-only, 16% for combination, and 29% for no treatment, whereas all-cause mean monthly total costs were $792, $633, $786, and $1,292, respectively. In multinomial logistic regression, age, sex, geographic region and urbanicity of patient residence, socioeconomic status, diagnosing provider specialty, and initial diagnosis location were significantly associated (P < 0.05) with treatment modality. In multivariable logistic regression, recipients of Rx-only (odds ratio = 2.03, P < 0.01) or combination (odds ratio = 3.26, P < 0.01) had higher odds of improving MDD severity than patients who received no treatment. CONCLUSIONS: In this real-world sample of commercially insured patients, we observed variations in outcomes by treatment modality and an association between treatment modality and disease severity. Further research is needed to explore the underlying causal relationships between treatment modality and patient outcomes. Study Registration: https://doi.org/10.17605/OSF.IO/YQ6B3 DISCLOSURES: Dr Grabner is an employee of Carelon Research, which received funding from the Innovation and Value Initiative for the conduct of the study on which this manuscript is based. Ms Pizzicato and Mr Yang were employees of Carelon Research at the time the study was conducted. Dr Grabner is a shareholder of Elevance Health. Drs Xie and Chapman are employees of the Innovation and Value Initiative.

Global translational control by the transcriptional repressor TrcR in the filamentous cyanobacterium Anabaena sp. PCC 7120.

Transcriptional and translational regulations are important mechanisms for cell adaptation to environmental conditions. In addition to house-keeping tRNAs, the genome of the filamentous cyanobacterium Anabaena sp. strain PCC 7120 (Anabaena) has a long tRNA operon (trn operon) consisting of 26 genes present on a megaplasmid. The trn operon is repressed under standard culture conditions, but is activated under translational stress in the presence of antibiotics targeting translation. Using the toxic amino acid analog ß-N-methylamino-L-alanine (BMAA) as a tool, we isolated and characterized several BMAA-resistance mutants from Anabaena, and identified one gene of unknown function, all0854, named as trcR, encoding a transcription factor belonging to the ribbon-helix-helix (RHH) family. We provide evidence that TrcR represses the expression of the trn operon and is thus the missing link between the trn operon and translational stress response. TrcR represses the expression of several other genes involved in translational control, and is required for maintaining translational fidelity. TrcR, as well as its binding sites, are highly conserved in cyanobacteria, and its functions represent an important mechanism for the coupling of the transcriptional and translational regulations in cyanobacteria.

A case report and literature review on respiratory failure with immune checkpoint inhibitors: a life-threatening adverse event.

Neuromuscular associated respiratory failure is a rare toxicity of immunotherapy for malignant tumors. In most cases, it may overlap with the symptoms of the primary disease or myocarditis, myositis and myasthenia gravis, resulting in difficult etiological diagnosis. Early detection and optimal treatment are still topics that need attention. Here, a case of 51-year-old male lung cancer patient with sintilimab-associated myasthenia gravis, myositis, and myocarditis overlap syndrome involving the diaphragm who developed severe type II respiratory failure was reported. After high-dose methylprednisolone, immunoglobulin and pyridostigmine intravenous injection with non-invasive positive pressure ventilation, the patient's symptoms improved significantly and was discharged. One year later, the patient received immunotherapy again due to tumor progression. After 53 days, he developed dyspnea again. Chest X-ray demonstrated marked elevation of the diaphragm, and the electromyogram demonstrated dysfunction of diaphragm. With rapid diagnosis and timely treatment, the patient was finally discharged safely. A comprehensive search of PubMed, EMBASE was performed to identify all previously reported cases of immune checkpoint inhibitors-associated respiratory failure. The potential mechanisms of respiratory failure caused by ICI-associated diaphragmatic dysfunction may be related to T cell-mediated immune disturbances and we proposed possible diagnostic processes. For patients with unexplained respiratory failure who are receiving immunotherapy, standardized diagnostic strategies should be implemented immediately on admission before deciding whether to conduct a more invasive diagnostic procedure or empirical treatment.

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.

Bone marrow mesenchymal stem cell-derived exosomes loaded with miR-26a through the novel immunomodulatory peptide DP7-C can promote osteogenesis.

PURPOSE: As small bioactive molecules, exosomes can deliver osteogenesis-related miRNAs to target cells and promote osteogenesis. This study aimed to investigate miR-26a as a therapeutic cargo to be loaded into bone marrow stromal cell exosomes through a novel immunomodulatory peptide (DP7-C). METHODS: After transfecting BMSCs with DP7-C as a transfection agent, exosomes were extracted by ultracentrifugation from the culture supernatant of miR-26a-modified BMSCs. We then characterized and identified the engineered exosomes. The effect of the engineered exosomes on osteogenesis was then evaluated in vitro and in vivo, including transwell, wound healing, modified alizarin red staining, western blot, real-time quantitative PCR, and experimental periodontitis assays. Bioinformatics and data analyses were conducted to investigate the role of miR-26a in bone regeneration. RESULTS: The DP7-C/miR-26a complex successfully transfected miR-26a into BMSCs and stimulated them to release more than 300 times the amount of exosomes overexpressing miR-26a compared with the ExoNC group. Furthermore, exosomes loaded with miR-26a could enhance proliferation, migration, and osteogenic differentiation of BMSCs in vitro compared with the ExoNC and blank groups. In vivo, the ExomiR-26a group inhibited the destruction of periodontitis compared with the ExoNC and blank groups, as revealed by HE staining. Micro-CT indicated that treatment of ExomiR-26a increased the percent bone volume and the bone mineral density compared with those of the ExoNC (P < 0.05) and blank groups (P < 0.001). Target gene analysis indicated that the osteogenic effect of miR-26a is related to the mTOR pathway. CONCLUSION: miR-26a can be encapsulated into exosomes through DP7-C. Exosomes loaded with miR-26a can promote osteogenesis and inhibit bone loss in experimental periodontitis and serve as the foundation for a novel treatment strategy.

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.

Childhood asthma diagnoses declined during the COVID-19 pandemic in the United States.

BACKGROUND: Prior studies have documented declines in pediatric asthma exacerbations and asthma-related health care utilization during the COVID-19 pandemic, but less is known about the incidence of asthma during the pandemic. METHODS: We conducted a retrospective cohort study of children under age 18 without a prior diagnosis of asthma within a large US commercial claims database. Incident asthma was defined using a combination of diagnosis codes, location of services, and medication dispensing. Crude quarterly rates of asthma diagnosis per 1000 children were calculated, and the incidence rate ratio and 95% confidence interval were estimated for newly diagnosed asthma during versus before the pandemic using negative binomial regression, adjusted for age, sex, region, and season. RESULTS: Compared with 3 years prior to the pandemic, crude incident diagnosis rates of asthma decreased by 52% across the first four quarters of the US pandemic. The covariate-adjusted pandemic-associated incidence rate ratio was 0.47 (95% confidence interval 0.43, 0.51). CONCLUSIONS: New diagnoses of childhood asthma in the US declined by half during the first year of the pandemic. These findings raise important questions whether pandemic-related changes in infectious or other triggers truly altered the incidence of childhood asthma beyond the well-described disruptions in healthcare access.