Advantages and Limitations of the Body Mass Index (BMI) to Assess Adult Obesity.

Obesity reflects excessive fat deposits. At-risk individuals are guided by healthcare professionals to eat fewer calories and exercise more, often using body mass index (BMI; weight/height2) thresholds for screening and to guide progress and prognosis. By conducting a mini-narrative review of original articles, websites, editorials, commentaries, and guidelines, we sought to place BMI in the context of its appropriate use in population health, clinical screening, and monitoring in clinical care. The review covers studies and publications through 2023, encompassing consensus reviews and relevant literature. Recent consensus reviews suggest that BMI is a valuable tool for population surveys and primary healthcare screening but has limitations in predicting the risk of chronic diseases and assessing excess fat. BMI can guide nutritional and exercise counseling, even if it is inadequate for reliable individual risk prediction. BMI cut-offs must be reconsidered in populations of varying body build, age, and/or ethnicity. Since BMI-diagnosed overweight persons are sometimes physically and physiologically fit by other indicators, persons who are overweight on BMI should be more fully evaluated, diagnosed, and monitored with combined anthropometric and performance metrics to better clarify risks. The use of combined anthropometric and performance metrics involves integrating measurements of body composition with assessments of physical function and fitness to provide a more comprehensive evaluation of an individual's health and fitness status. Eligibility for bariatric surgery or semaglutide satiety/appetite-reduction medications should not be determined by BMI alone. Awareness of the advantages and limitations of using BMI as a tool to assess adult obesity can maximize its appropriate use in the context of population health and in rapid clinical screening and evaluation.

Long COVID Characteristics and Experience: A Descriptive Study from the Yale LISTEN Research Cohort.

OBJECTIVE: To describe the experience of people with long COVID symptomatology and characterize the psychological, social, and financial challenges they experience. BACKGROUND: The experience of people with long COVID needs further amplification, especially with a comprehensive focus on symptomatology, treatments, and impact on daily life and finances. METHODS: We collected data from individuals aged 18 and older reporting long COVID as participants in the Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study. The sample population included 441 participants surveyed between May 2022 and July 2023. We evaluated their demographic characteristics, socioeconomic and psychological status, index infection period, health status, quality of life, symptoms, treatments, pre-pandemic comorbidities, and new-onset conditions. RESULTS: Overall, the median age of the participants with long COVID was 46 years (IQR: 38 to 57 years); 74% were women, 86% were Non-Hispanic White, and 93% were from the United States. Participants reported low health status measured by the Euro-QoL visual analogue scale, with a median score of 49 (IQR: 32 to 61). Participants documented a diverse range of symptoms, with all 96 possible symptom choices being reported. Additionally, participants had tried many treatments (median number of treatments: 19, IQR: 12 to 28). They were also experiencing psychological distress, social isolation, and financial stress. CONCLUSIONS: Despite having tried numerous treatments, participants with long COVID continued to experience an array of health and financial challenges-findings that underscore the failure of the healthcare system to address the medical needs of people with long COVID. These insights highlight the need for crucial medical, mental health, financial, and community support services, as well as further scientific investigation, to address the complex impact of long COVID.

Quality of life and clinical correlates in cognitively-able autistic adults: A special focus on sensory characteristics and perceived parental support.

BACKGROUND: Quality of life (QoL) has been suggested as an indicator of outcomes in autistic adults. Factors associated with QoL in autistic individuals remain unclear. This study aims to examine the subjective QoL for autistic adults in Taiwan and investigate the determinants for different domains of QoL. METHODS: The study comprised 90 autistic adults (aged 26.9, SD 7.3; males, 80.9%). We used Taiwanese version of World Health Organization Quality of Life-BREF to measure QoL. Four domains of QoL were compared with 61 non-autistic controls, including physical, psychological, social, and environment. To identify the correlates of QoL domains, we assessed IQ, personality trait, family support, anxiety/depressive symptoms, autistic severity, and sensory symptoms by various questionnaires, and assessed their association with QoL by correlation analyses and model selection. RESULTS: Our results showed that autistic adults reported lower QoL on the World Health Organization Quality of Life (WHOQOL)-BREF across all domains. QoL was significantly associated with autistic symptom severity, harm avoidance, family support, sensory symptoms, anxiety, and depression, but not intelligence. Model selections revealed male sex, poor paternal support, autism severity, depression, anxiety, and sensory symptoms were associated with specific QoL domains. CONCLUSION: Findings supported lower QoL in autistic adults. Modifying the QoL correlates may improve life quality in autistic adults. Furthermore, our findings revealed the importance of sensory symptoms and paternal support in QoL of autistic adults, which was a novel finding in this population.

Factors Associated With Long COVID: Insights From Two Nationwide Surveys.

BACKGROUND: Long COVID is a multisystemic condition that affects the lives of millions of people globally, yet factors associated with it are poorly defined. Our purpose in this study was to identify factors associated with long COVID. METHODS: This cross-sectional study used data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and the 2022 National Health Interview Survey (NHIS). We restricted the sample to individuals aged 18 and older who reported a positive COVID-19 test or doctor's diagnosis. Individuals who reported symptoms of at least 3 months were assumed to have long COVID. We identified demographic and clinical characteristics associated with long COVID, in unadjusted and adjusted analyses. RESULTS: The study included 124,313 individuals in the BRFSS cohort and 10,131 in the NHIS cohort who reported a COVID-19 infection, with 26,783 (21.5%) and 1797 (17.7%) reporting long COVID, respectively. We found middle age, female sex, lack of a college degree, and severity of acute COVID-19 infection to be associated with long COVID. In contrast, non-Hispanic Asian and Black Americans were less likely to report long COVID compared with non-Hispanic White individuals. These findings were consistent across datasets. CONCLUSIONS: Several demographic features were associated with long COVID, which may be the result of social, clinical, or biological influences.

Stereoselectivity of paclobutrazol enantiomers to oxidative stress in wheat.

Chiral pesticides have the special chiral structures, so enantioselective biological effects are usually observed in living organisms. Current study used paclobutrazol as a case study and explored the enantioselective degradation and oxidative stress effect on wheat. The results demonstrated that the degradation of R-paclobutrazol was faster than S-paclobutrazol significantly and improved the content of MDA and O2 - in wheat plants, which proved that the R-paclobutrazol induced oxidative damage in wheat, showing selective biological effects, and S-paclobutrazol was friendly to wheat. This study provided a theoretical basis for the selective activity of chiral pesticides and the development of chiral pesticide monomers.

Role of c-Fos in DNA damage repair.

c-Fos, a member of the immediate early gene, serves as a widely used marker of neuronal activation induced by various types of brain damage. In addition, c-Fos is believed to play a regulatory role in DNA damage repair. This paper reviews the literature on c-Fos' involvement in the regulation of DNA damage repair and indicates that genes of the Fos family can be induced by various forms of DNA damage. In addition, cells lacking c-Fos have difficulties in DNA repair. c-Fos is involved in tumorigenesis and progression as a proto-oncogene that maintains cancer cell survival, which may also be related to DNA repair. c-Fos may impact the repair of DNA damage by regulating the expression of downstream proteins, including ATR, ERCC1, XPF, and others. Nonetheless, the underlying mechanisms necessitate further exploration.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome, and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme, and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids, and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of functional profiles derived from gut microbiota, with the CAZyme genes being the top performing model to accurately predict early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster-tryptophan and B cell cluster-tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may be of etiological and diagnostic implications in CKD.

Enhancing osteosarcoma therapy through aluminium hydroxide nanosheets-enabled macrophage modulation.

Chemotherapy in osteosarcoma treatment has long been stagnating, leaving challenges in the treatment of patients with metastatic and recurrent osteosarcoma. Modulation of macrophages in the tumour microenvironment offers great opportunities to elicit a durable antitumour effect. Here, we employed aluminium hydroxide nanosheets (nAl) to co-deliver the chemotherapy drug doxorubicin (DOX) and immune modulator zoledronic acid (ZA). The hexagon nAl was obtained by a facile approach, with a high positive surface charge for the loading of ZA. With 37% and 8.5% payloads to ZA and DOX, the formed nAl/ZD showed efficient cell growth inhibition to LM8 osteosarcoma cells, and preferential M1 polarization induction to RAW 264.7 macrophage cells. Furthermore, enhanced antitumour effect was observed with nAl/ZD-enabled macrophage activation in the LM8/RAW 264.7 co-culture model. Our results may inspire new treatment strategies for osteosarcoma.

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization.

Introduction: A chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized. Methods: We included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience. Results: The median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition. Conclusions: In this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

Sustainable Optimal Control for Switched Pollution-Control Problem with Random Duration.

Considering the uncertainty of game duration and periodic seasonal fluctuation, an n-player switched pollution-control differential game is modeled to investigate a sustainable and adaptive strategy for players. Based on the randomness of game duration, two scenarios are considered in this study. In the first case, the game duration is a random variable, Tf, described by the shifted exponential distribution. In the second case, we assumed that players' equipment is heterogeneous, and the i-th player's equipment failure time, Tfi, is described according to the shifted exponential distribution. The game continues until a player's equipment breaks down. Thus, the game duration is defined as Tf=min{Tf1,…,Tfn}. To achieve the goal of sustainable development, an environmentally sustainable strategy and its corresponding condition are defined. By using Pontryagin's maximum principle, a unique control solution is obtained in the form of a hybrid limit cycle, the state variable converges to a stable hybrid limit cycle, and the total payoff of all players increases and then converges. The results indicate that the environmentally sustainable strategy in the n-player pollution-control cooperative differential game with switches and random duration is a unique strategy that not only ensures profit growth but also considers environmental protection.

GPR65 inhibits human trophoblast cell adhesion through upregulation of MYLK and downregulation of fibronectin via cAMP-ERK signaling in a low pH environment.

BACKGROUND: Extravillous trophoblasts (EVTs) are essential cells during the formation of the placenta, with the major function of invading the maternal decidua, anchoring the developing placenta to the uterus, remodeling uterine arteries, and regulating immune responses to prevent rejection. During early pregnancy, the decidua undergoes a hypoxic and acidic microenvironment, which has been shown to participate in tumor cell migration, invasion, growth, and angiogenesis. Nevertheless, the mechanisms by which EVTs sense and respond to the acidic microenvironment, thereby executing their functions, remain poorly understood. METHODS: The effects of G protein-coupled receptor 65 (GPR65) on cell adhesion and other cellular functions were tested using JAR spheroids, mouse blastocysts, and HTR-8/SVneo cells. Specifically, we employed HTR-8/SVneo cells for gene overexpression and silencing to investigate the underlying mechanism of GPR65's impact on trophoblast cell function under acidic conditions. Additionally, villus tissue samples obtained from early pregnancy loss patients were utilized to explore the potential association between GPR65 and its related signaling pathway molecules with the disease. RESULTS: This study identified GPR65 expression widely in trophoblasts, with the highest level in EVTs. Importantly, optimal GPR65 levels are required for maintaining normal adhesion, migration, and invasion, whereas overexpression of GPR65 inhibits these functions by activating the cAMP-ERK signaling pathway, upregulating myosin light chain kinase (MYLK) and MYLK3 expression, and subsequently downregulating fibronectin. Consistently, elevated expression of GPR65, MYLK, and MYLK3 is observed in patients suffering from early pregnancy loss. CONCLUSIONS: This work offers insights into the suppressive effects of GPR65 on EVT function under acidic conditions and highlights a putative target for therapeutic intervention in early pregnancy complications. Video Abstract.

The association between admission serum albumin and preoperative deep venous thrombosis in geriatrics hip fracture: a retrospective study of 1819 patients with age ≥ 65 years.

OBJECTIVE: This study evaluated the association between serum albumin levels and preoperative deep vein thrombosis (DVT) in geriatric hip fractures. METHODS: Older adult patients with hip fractures were screened between January 2015 and September 2019. The demographic and clinical characteristics of the patients were collected. Multivariate binary logistic regression and generalized additive model were used to identify the linear and nonlinear association between albumin levels and preoperative DVT. Analyses were performed using EmpowerStats and the R software. RESULTS: A total of 1819 patients were included in this study. The average age was 79.37 ± 6.88 years. There were 550 males and 1269 females. The preoperative albumin was 38.19 ± 4.07 g/L. There were 580 (31.89%) preoperative DVTs. Multivariate binary logistic regression showed that albumin level was associated with preoperative DVT (odds ratio [OR] = 0.94, 95% confidence interval [CI]: 0.91-0.97, P = 0.0002) after adjusting for confounding factors. The fully adjusted model showed a DVT risk decrease of 6% when albumin concentration increased by one g/L after controlling for confounding factors. In addition, the trend test and propensity score matching also showed a stable linear correlation between albumin level and preoperative DVT. CONCLUSION: Serum albumin is associated with preoperative DVT in geriatric patients with hip fractures, and it could be considered a predictor for the risk of DVT. REGISTRATION ID: ChiCTR2200057323.

Enhanced Cartilage and Subchondral Bone Repair Using Carbon Nanotube-Doped Peptide Hydrogel-Polycaprolactone Composite Scaffolds.

A carbon nanotube-doped octapeptide self-assembled hydrogel (FEK/C) and a hydrogel-based polycaprolactone PCL composite scaffold (FEK/C3-S) were developed for cartilage and subchondral bone repair. The composite scaffold demonstrated modulated microstructure, mechanical properties, and conductivity by adjusting CNT concentration. In vitro evaluations showed enhanced cell proliferation, adhesion, and migration of articular cartilage cells, osteoblasts, and bone marrow mesenchymal stem cells. The composite scaffold exhibited good biocompatibility, low haemolysis rate, and high protein absorption capacity. It also promoted osteogenesis and chondrogenesis, with increased mineralization, alkaline phosphatase (ALP) activity, and glycosaminoglycan (GAG) secretion. The composite scaffold facilitated accelerated cartilage and subchondral bone regeneration in a rabbit knee joint defect model. Histological analysis revealed improved cartilage tissue formation and increased subchondral bone density. Notably, the FEK/C3-S composite scaffold exhibited the most significant cartilage and subchondral bone formation. The FEK/C3-S composite scaffold holds great promise for cartilage and subchondral bone repair. It offers enhanced mechanical support, conductivity, and bioactivity, leading to improved tissue regeneration. These findings contribute to the advancement of regenerative strategies for challenging musculoskeletal tissue defects.

Quality of life after surgery for lower grade gliomas.

BACKGROUND: Few large studies have investigated quality of life (QOL) for adults diagnosed with lower grade glioma (LGG). METHODS: QOL was assessed for 320 adults with LGG (World Health Organization grade 2/3) enrolled in the International Low Grade Glioma Registry by using the Medical Outcomes Study 36-Item Short Form health survey. Data on symptoms were also collected. QOL outcomes were examined by treatment group and also compared to those from a population-based case-control study of meningioma (the Meningioma Consortium), in which 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013 were enrolled and frequency matched to 1622 controls by age, sex, and geography. RESULTS: The LGG sample average age is 45 years at the time of interview and 53.1% male. Almost 55% of patients had received radiation and chemotherapy (primarily temozolomide); 32.4% had received neither treatment. Two-thirds of participants with LGG report difficulty with speaking, memory, or thinking, and over one of three reports personality change or difficulty driving. After controlling for age and other comorbidities, individuals with LGG report levels of physical, emotional, and mental health functioning below those reported in a meningioma as well as a general healthy population. CONCLUSIONS: Despite being relatively young, persons with LGG report significantly reduced QOL compared to persons with nonmalignant brain tumors and to a control population, which highlights the need to better acknowledge and manage these symptoms for this group of patients diagnosed in the prime of life.

lncRNA CLRN1-AS1 reduces adhesion ability of human trophoblasts via CXCL10/CXCL11.

INTRODUCTION: Trophoblast cells play an important role in embryo recognition and localization, as well as placental development during embryo implantation. Dysfunction of trophoblastic cells causes pathological changes that lead to insufficient recognition, positioning, and adhesion during embryo implantation, ultimately leading to embryo development has stopped. METHODS: High-throughput sequencing was used to identify differentially expressed the mRNA and lncRNA in the villi tissue of pregnant women diagnosed with embryo cessation. In vitro implantation cell models, characteristic analysis, and bio information analysis confirmed that CLRN1-AS1 affected the adhesion function of trophoblast cells by influencing the chemokines CXCL10/CXCL11. RESULTS: High throughput sequencing technology was used to identify 438 differentially expressed mRNAs and 41 lncRNAs. The three lncRNAs, namely CLRN1-AS1, USP27X-AS1, and AC104809.4, were screened by the mRNA-lncRNA network. In vitro implantation model suggested that all three lncRNAs could affect the adhesion between trophoblast cells, among which CLRN1-AS1 had the most significant effect. Characteristic analysis and correlation analysis showed that CLRN1-AS1 was closely related to the expression of six adhesion-related genes, LAMA1, FGL2, ITGB2, FBN1, EMP2, and PODN. Cell experiments and re-sequencing confirmed that CLRN1-AS1 could affect the adhesion ability of trophoblast cells to the extracellular matrix, and its process was related to the chemokine CXCL10/CXCL11. DISCUSSION: These results constructed the network of mRNA-lncRNA and enrichment when embryonic development has stopped and found CLRN1-AS1 highly correlated to failure of embryo implantation, and revealed that CLRN1-AS1 modulates the adhesion ability of trophoblast cells to the extracellular matrix via the chemokines CXCL10/CXCL11 during the early stage of embryo implantation.

Clinical Efficacy of the Huo Xue Hua Yu Method Combined with Aspirin in the Treatment of Acute Cerebral Infarction: A Systematic Evaluation and Meta-analysis.

OBJECTIVE: The study aimed to evaluate the clinical efficacy of the Huo Xue Hua Yu method combined with aspirin in the treatment of patients with acute cerebral infarction (ACI). METHODS: By searching electronic databases, such as the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure Database (CNKI), the China Science and Technology Journal Database, Wanfang, PubMed, Embase, and the Cochrane Library, all randomized controlled trials (RCTs) published before 14 July, 2022, and published in Chinese or English languages were selected. Statistical analysis was performed using Review Manager 5.4 calculation software to calculate the odds ratio (OR), mean difference (MD), 95% confidence interval (CI), and p values. RESULTS: 13 articles that included 1,243 patients were identified; in 646 of them, the Huo Xue Hua Yu method combined with aspirin has been administered, while 597 have only been administered aspirin therapy. The combined treatment significantly improved clinical efficacy (OR: 4.41, 95% CI: 2.90 to 5.84, p < 0.001, I2 = 0), as assessed by the National Institutes of Health Stroke Scale score (MD = -4.18, 95% CI: -5.69 to -2.67, p < 0.001, I2 = 94%), Barthel score (MD = -2.23, 95% CI: -2.66 to -1.81, p < 0.001, I2 = 82%), the China Stroke Scale score (MD = 6.74, 95% CI: -3.49 to 16.96, P = 0.20, I2 = 99%), packed cell volume (MD = -8.45, 95% CI: -8.81 to -8.09, p < 0.001, I2 = 98%), fibrinogen levels (MD = -0.93, 95% CI: -1.23 to -0.63, p < 0.001, I2 = 78%) and plasma viscosity (MD = -0.51, 95% CI: -0.72 to -0.30, p < 0.001, I2 = 62%). CONCLUSION: The combination of the Huo Xue Hua Yu method and aspirin represents a beneficial adjunctive therapy for ACI.

Deep immune profiling of patients with renal impairment unveils distinct immunotypes associated with disease severity.

Background: Chronic kidney disease (CKD) is pathologically correlated with a sophisticated milieu of innate and adaptive immune dysregulation, but the underlying immunological disturbances remain poorly understood. Methods: To address this, we comprehensively interrogated cellular and soluble elements of the immune system by using high-dimensional flow cytometry to analyze peripheral blood mononuclear cells and performing cytokine/chemokine profiling of serum samples, respectively, in a cohort of 69 patients and 19 non-CKD controls. Results: Altered serum levels of several cytokines/chemokines were identified, among which concentrations of stem cell factor (SCF) were found to be elevated with the progression of CKD and inversely correlated with estimated glomerular filtration rate (eGFR). Deep immunophenotyping analyses reveal a global change in immune modulation associated with CKD severity. Specifically, a decrease in the subsets of CD56dim natural killer (NK) cells (KLRG-1+CD38+CD64+CD15+CD197+) and monocytes (KLRG-1+CD38+PD-1+) was detected in severe CKD compared with controls and mild CKD. In addition, comparisons between mild and severe CKD demonstrated a loss of a mature B cell population (PD-1+CD197+IgD+HLA-DR+) in the advanced stages of disease. Further, we identified immunophenotypic markers to discriminate mild CKD from the controls, among which the portion of CD38+ monocytes was of particular value in early diagnosis. Conclusions: Our data unveil severity-specific immunological signatures perturbed in CKD patients.

Cell-free and cytokine-free self-assembling peptide hydrogel-polycaprolactone composite scaffolds for segmental bone defects.

Segmental bone defects over the self-healing threshold are a major challenge for orthopedics. Despite the advancements in clinical practice, traditional tissue engineering methods are limited by the addition of heterogeneous cells and cytokines, leading to carcinoma or other adverse effects. Here, we present a cell-free and cytokine-free strategy using an ECM-mimetic self-assembling peptide hydrogel (SAPH)- polycaprolactone (PCL) composite scaffold. The hydrophilic SAPH endows the rigid PCL scaffold with excellent biocompatibility and preference for osteogenesis induction. The autologous cells around the bone defect site immediately grew, proliferated, and secreted ECM and cytokines after contacting the implanted SAPH-PCL composite scaffold, and the bone repair of rabbit ulnar segmental bone defect was achieved in just six months. Quantitative proteomic analysis reveals that the SAPH-PCL composite scaffold accelerates osteoblastogenesis, osteoclastogenesis, and angiogenesis with moderate immune responses and negligible effects on pathological fibrosis. These findings have important implications for the potential clinical applications of the SAPH-PCL composite scaffold in patients with segmental bone defects and identify the mechanisms of action for accelerated segmental bone defect repair.

Discovery of antipsychotic loxapine derivatives against intracellular multidrug-resistant bacteria.

The emergence and spread of multidrug-resistant bacteria highlight the need for new antibacterial interventions. A screening of 24 newly synthesized dibenzoxazepines identified a small molecule compound, SW14, with potent inhibitory activity against intracellular multidrug-resistant and fluoroquinolone-resistant strains of S. typhimurium in macrophages and epithelial cells. Moreover, intra-macrophagic Salmonella typhi, Yersinia enterocolitica, and Listeria monocytogenes and methicillin-resistant Staphylococcus aureus are also susceptible to SW14. Overall, our findings suggest that SW14 has a broad-spectrum activity against intracellular bacteria.

Intranasal Delivery of RIG-I Agonist Drives Pulmonary Myeloid Cell Activation in Mice.

Viral respiratory infections cause substantial health and economic burden. There is a pressing demand for efficacious vaccination strategies and, therefore, a need for a better understanding of the mechanisms of action of novel potential adjuvants. Here we investigated the effect of a synthetic RIG-I agonist, the dsRNA hairpin 3p10LA9, on the activation of pulmonary myeloid cells. Analysis of early innate immune responses revealed that a single intranasal 3p10LA9 dose induces a transient pulmonary interferon-stimulated gene (ISG) and pro-inflammatory cytokine/chemokine response, which leads to the maturation of three distinct dendritic cell subpopulations in the lungs. While lung resident dendritic cell decrease shortly after 3p10LA9 delivery, their numbers increase in the draining mediastinal lymph node, where they have migrated, maintaining their activated phenotype. At the same time, dsRNA hairpin-induced chemokines attract transiently infiltrating monocytes into the lungs, which causes a short temporary pulmonary inflammation. However, these monocytes are dispensable in controlling influenza infection since in CCR2 deficient mice, lacking these infiltrating cells, the virus load was similar to the wild type mice when infected with the influenza virus at a sublethal dose. In summary, our data suggest that intranasal delivery of dsRNA hairpins, used as a RIG-I targeting adjuvant, represents an attractive strategy to boost type I inteferon-mediated lung dendritic cell maturation, which supports viral reduction in the lungs during infection.