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The final and rate-limiting enzyme in pyrimidine biosynthesis, CTP synthase (CTPS) , is essential for the viability of Mycobacterium tuberculosis and other mycobacteria. Its product, CTP, is critical for RNA, DNA, lipid and cell wall synthesis, and is involved in chromosome segregation. In various organisms across the tree of life, CTPS assembles into higher-order filaments, leading us to hypothesize that M. tuberculosis CTPS (mtCTPS) also forms higher-order structures. Here, we show that mtCTPS does assemble into filaments but with an unusual architecture not seen in other organisms. Through a combination of structural, biochemical, and cellular techniques, we show that polymerization stabilizes the active conformation of the enzyme and resists product inhibition, potentially allowing for the highly localized production of CTP within the cell. Indeed, CTPS filaments localize near the CTP-dependent complex needed for chromosome segregation, and cells expressing mutant enzymes unable to polymerize are altered in their ability to robustly form this complex. Intriguingly, mutants that alter filament formation are under positive selection in clinical isolates of M. tuberculosis, pointing to a critical role needed to withstand pressures imposed by the host and/or antibiotics. Taken together, our data reveal an unexpected mechanism for the spatially organized production of a critical nucleotide in M. tuberculosis, which may represent a vulnerability of the pathogen that can be exploited with chemotherapy.
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The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.
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Ceramidasa Alcalina , Proteínas de Transporte de Catión , Enfermedades Inflamatorias del Intestino , Mucosa Intestinal , Manganeso , Ratones Noqueados , Animales , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Manganeso/metabolismo , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ceramidasa Alcalina/metabolismo , Ceramidasa Alcalina/genética , Humanos , Ratones Endogámicos C57BL , Homeostasis , Masculino , Colitis/metabolismo , Colitis/genética , Colitis/patología , Absorción Intestinal , Células Epiteliales/metabolismoRESUMEN
BACKGROUND: Physical inactivity is prevalent after cancer treatment, which could increase ischemic stroke risk in cancer survivors. This study investigated the association between physical activity change from pre- to post-diagnosis and ischemic stroke risk among cancer survivors. METHODS: Using data from the Korean National Health Insurance Service database, 269,943 cancer survivors (mean [SD] age, 56.3 [12.1] years; 45.7% male) with no history of cardiovascular disease were evaluated based on changes in physical activity from pre- to post-diagnosis. Using the Fine-Gray model, subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs) for ischemic stroke risk were calculated, considering death as a competing risk. RESULTS: After cancer diagnosis, 62.0% remained inactive, 10.1% remained active, 16.6% became active, and 11.4% became inactive. During a mean (SD) follow-up of 4.1 (2.0) years, being active both pre- and post-diagnosis was associated with a 15% decreased risk of ischemic stroke (sHR, 0.85; 95% CI, 0.75-0.96), compared with those who remained inactive. Cancer survivors who became active and inactive post-diagnosis showed a 16% and 11% lower ischemic stroke risk (sHR, 0.84; 95% CI, 0.75-0.93; sHR, 0.89; 95% CI, 0.79-0.99), respectively, than those who remained inactive. Analysis by the primary cancer site did not substantially differ from the main findings. CONCLUSIONS: Physical activity is associated with reduced ischemic stroke risk among cancer survivors. The potential benefits of physical activity are not limited to individuals who were physically active before cancer diagnosis, thus preventive strategies against ischemic stroke should emphasize physical activity throughout the cancer journey.
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Ejercicio Físico , Accidente Cerebrovascular Isquémico , Neoplasias , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Neoplasias/epidemiología , Neoplasias/complicaciones , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Anciano , Factores de Riesgo , Adulto , Supervivientes de Cáncer/estadística & datos numéricos , República de Corea/epidemiología , Incidencia , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND: Patients with Lumbar Spinal Stenosis (LSS) typically complain of back pain and leg pain. These symptoms reduce the quality of life (QoL) and also cause sleep disturbances. This study compares pregabalin and limaprost's efficacy in LSS for pain, disability, QoL, and sleep, aiming to offer insights for medication selection. METHODS: This study was designed as a prospective, randomized, single-center, single-blinded, clinical superiority trial targeting patients with LSS. For 6 weeks, 111 patients per group were administered medication following a standard regimen, after which patient-reported outcomes were measured. The primary outcome was the Visual Analogue Scale (VAS) for back and leg pain, and the secondary outcomes included the Oswestry Disability Index (ODI), European Quality of Life 5 Dimensions (EQ-5D), and sleep quality. RESULTS: After 6 weeks of medication, there were significant improvements over time in the primary outcome, VAS for back pain and leg pain, in both groups, but no significant difference between the 2 groups. Similarly, for the secondary outcomes, ODI and EQ-5D, both groups showed significant improvements, yet there was no significant difference between them. In the subgroup analysis targeting poor sleepers (Pittsburgh sleep quality index, PSQI >5), both groups also exhibited significant improvements in sleep quality, but again, there was no significant difference between the groups. CONCLUSIONS: Efficacy of pregabalin, limaprost in back and leg pain, ODI, EQ-5D, and sleep quality, but there was no significant difference between the 2 groups. Thus, it is advisable to prescribe based on individual drug responses and potential complications.
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Analgésicos , Vértebras Lumbares , Pregabalina , Calidad de Vida , Estenosis Espinal , Humanos , Pregabalina/uso terapéutico , Estenosis Espinal/tratamiento farmacológico , Estenosis Espinal/complicaciones , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Método Simple Ciego , Analgésicos/uso terapéutico , Alprostadil/análogos & derivados , Alprostadil/uso terapéutico , Dimensión del DolorRESUMEN
PURPOSE: Identifying and managing risk factors for lower urinary tract symptoms (LUTS) is crucial because it impacts the quality of life of elderly individuals. Lifestyle factors, including physical activity (PA), and their relationship with LUTS have not been well studied. This objective of this study was to investigate the association between PA and LUTS. MATERIALS AND METHODS: A total of 7,296 men were included in this cross-sectional study. PA was quantified in metabolic equivalent (MET)-hours per week, and LUTS severity was assessed using the international prostate symptom score. Logistic regression was used to analyze the association between PA and LUTS, including voiding and storage symptoms. RESULTS: The average age of the participants was 57.8 years, and the prevalence of LUTS was 41.3%. After adjusting for potential confounders, PA was inversely associated with the prevalence and severity of moderate-to-severe LUTS, showing a dose-response pattern (all p for trend <0.01). Compared to the minimal activity group, which engaged in <5 MET-hours per week of PA, the odds ratios for moderate to severe LUTS were 0.83 (95% confidence interval [CI]: 0.72-0.97) for men engaging in 15-30 MET-hours per week, 0.82 (95% CI: 0.71-0.95) for 30-60 MET-hours per week, and 0.72 (95% CI: 0.62-0.84) for ≥60 MET-hours per week. The possible protective effect of PA was still observed in the additional analysis for voiding and storage symptoms showing the same dose-response pattern (all p for trend <0.01). CONCLUSIONS: A higher PA level was associated with a lower prevalence and severity of total, voiding, and storage LUTS in a dose-dependent manner in Korean men.
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The aim of this preliminary study was to assess the impact of injecting recombinant human bone morphogenetic protein-2 (rhBMP-2) with ß-tricalcium phosphate (ß-TCP) carrier into the uppermost instrumented vertebra (UIV) during surgery to prevent the development of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF). The 25 patients from study group had received 0.5 mg rhBMP-2 mixed with 1.5 g ß-TCP paste injection into the UIV during surgery. The control group consisted of 75 patients who underwent surgery immediately before the start of the study. The incidences of PJK and PJF were analyzed as primary outcomes. Spinopelvic parameters and patient-reported outcomes were analyzed as secondary outcomes. Hounsfield unit (HU) measurements were performed to confirm the effect of rhBMP-2 with ß-TCP on bone formation at preoperative and postoperative at computed tomography. PJK and PJF was more occurred in control group than study group (p = 0.02, 0.29, respectively). The HU of the UIV significantly increased 6 months after surgery. And the increment at the UIV was also significantly greater than that at the UIV-1 6 months after surgery. Injection of rhBMP-2 with ß-TCP into the UIV reduced PJK and PJF rates 6 months after surgery with new bone formation.
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Proteína Morfogenética Ósea 2 , Fosfatos de Calcio , Cifosis , Proteínas Recombinantes , Fusión Vertebral , Factor de Crecimiento Transformador beta , Adulto , Humanos , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Cifosis/etiología , Fusión Vertebral/métodosRESUMEN
OBJECTIVES: Little is known about the disparities in underweight prevalence among the general population in high-income countries. We investigated the trends in underweight prevalence and disparities across sociodemographic groups among Korean adults and older adults. SETTING AND PARTICIPANTS: A series of cross-sectional data on Korean national health checkups for adults aged ≥20 years were analyzed from 2005 to 2016. MEASUREMENTS: Based on body mass index (kg/m2), underweight was graded as mild (17.0-18.49), moderate (16.0-16.9), and severe (<16.0). Underweight prevalence was compared across sociodemographic subgroups in 2015-2016. Trends in underweight disparities were examined from 2005-2006 to 2015-2016. Multivariable-adjusted odds ratios (ORs; 95% confidence intervals, CIs) were calculated using logistic regression. RESULTS: Approximately 11-22 million adults were included in each wave. In 2015-2016, the overall prevalence of underweight was 3.6% (men 2.0%, women 5.2%); severe underweight was 0.2% (men 0.1%, women 0.3%). The prevalence of underweight varied by sex and age groups. In men, those aged ≥80 years had the highest prevalence (overall 7.33%, severe underweight 0.84%). In women, those aged 20-29 years had the highest prevalence of overall underweight (14.57%), whereas those aged ≥80 years had the highest prevalence of severe underweight (1.38%). Compared with individuals in the lowest income quartile, men in the highest income had lower ORs of overall (0.59, 95% CI 0.59-0.60) and severe underweight (0.46, 95% CI 0.44-0.48); women in the highest income quartile had a higher OR of overall (1.12, 95% CI 1.12-1.13) but a lower OR of severe underweight (0.89, 95% CI 0.86-0.92). From 2005-2006 to 2015-2016, severe underweight consistently declined in older men but remained constant in women aged ≥80 years, widening sex disparities among older adults. Severe underweight decreased or leveled off in the highest income quartile but steadily increased in the lowest quartile, worsening income disparities. CONCLUSION: In this nationwide study, underweight was more prevalent among women, older adults aged ≥80 years, and low-income individuals. Disparities in severe underweight widened across sociodemographic subgroups over time.
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Índice de Masa Corporal , Delgadez , Humanos , Delgadez/epidemiología , Masculino , Femenino , Estudios Transversales , República de Corea/epidemiología , Adulto , Anciano , Persona de Mediana Edad , Prevalencia , Anciano de 80 o más Años , Adulto Joven , Disparidades en el Estado de Salud , Factores Socioeconómicos , Factores SexualesRESUMEN
BACKGROUND: Chronic atrophic gastritis causes hypochlorhydria, hypergastrinemia, and malabsorption of nutrients, leading to lower bone mineral density. The few studies that investigated the association between chronic atrophic gastritis and bone mineral density have reported inconsistent findings. As such, the present study assessed the association between chronic atrophic gastritis and bone mineral density among a large sample of women >40 years of age in Korea. METHODS: Data from 8,748 women >40 years of age who underwent esophagogastroduodenoscopy and bone densitometry were analyzed. Chronic atrophic gastritis was diagnosed using esophagogastroduodenoscopy. Bone mineral density of the lumbar vertebrae (L), femur neck, and femur total, measured using dual-energy X-ray absorptiometry, were the primary outcome variables. Low bone mineral density, which could be diagnosed as osteoporosis or osteopenia, was defined and analyzed as a secondary outcome. Linear regression was used to calculate adjusted mean values of bone mineral density. The association between low bone mineral density and chronic atrophic gastritis was analyzed using multiple logistic regression. RESULTS: The adjusted mean bone mineral density for L1-L4 was 1.063±0.003, femur neck (0.826±0.002), and femur total (0.890±0.002) were significantly lower in patients with chronic atrophic gastritis than others (1.073±0.002, 0.836±0.001, 0.898±0.002, respectively; all P<0.01). Women with chronic atrophic gastritis exhibited an increased likelihood for osteopenia or osteoporosis, even after adjusting for age and other confounding factors (odds ratio, 1.25; 95% confidence interval, 1.13-1.40; P<0.01). However, subgroup analysis revealed statistical significance only in postmenopausal women (odds ratio, 1.27; P<0.001). CONCLUSION: Chronic atrophic gastritis was associated with lower bone mineral density and a higher risk for osteopenia or osteoporosis among postmenopausal women.
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Thin-film thermocouple (TFTC) technology is a novel measurement method that produces a thermocouple sensor during the deposition process, even though it is a complex surface, to obtain the surface temperature. TFTC is a thin film sensor for measuring temperature by contact methods, consisting of two different metals which can generate thermoelectric forces named "Seebeck effects". In the past decade there have been many attempts to measure the cutting temperature during machining processes using TFTF sensors. However, research has not yet progressed to optimize the sensor performance or fabrication process. This paper studies a preliminary technique for the fabrication of a TFTC sensor on a cutting tool surface and optimizes the deposition conditions, TFTC design, and sensor performance. Chromel and Alumel, which are materials commonly used in K-type thermocouples, were used for the thermal evaporation process. When the Chromel has a nickel to chrome ratio of 9:1, low resistivity and minimal variation with increasing temperature were observed. When the contact area of the deposited electrode (+) and (-) poles increased, the resistivity decreased and the TFTC sensitivity improved. Data acquisition tests using a DAQ system connected to the TFTC sensor show the lowest resistivity in TFTC B and C types are able to measure temperature data. It is expected that the heat generated during the cutting process can be detected using the TFTC sensor with B-type shape and Chromel with a 9:1 nickel to chrome ratio.
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Although three-dimensional (3D) printing techniques are used to mimic macro- and micro-structures as well as multi-structural human tissues in tissue engineering, efficient target tissue regeneration requires bioactive 3D printing scaffolds. In this study, we developed a bone morphogenetic protein-2 (BMP-2)-immobilized polycaprolactone (PCL) 3D printing scaffold with leaf-stacked structure (LSS) (3D-PLSS-BMP) as a bioactive patient-tailored bone graft. The unique LSS was introduced on the strand surface of the scaffold via heating/cooling in tetraglycol without significant deterioration in physical properties. The BMP-2 adsorbed on3D-PLSS-BMPwas continuously released from LSS over a period of 32 d. The LSS can be a microtopographical cue for improved focal cell adhesion, proliferation, and osteogenic differentiation.In vitrocell culture andin vivoanimal studies demonstrated the biological (bioactive BMP-2) and physical (microrough structure) mechanisms of3D-PLSS-BMPfor accelerated bone regeneration. Thus, bioactive molecule-immobilized 3D printing scaffold with LSS represents a promising physically and biologically activated bone graft as well as an advanced tool for widespread application in clinical and research fields.
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Osteogénesis , Andamios del Tejido , Humanos , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Regeneración Ósea , Poliésteres/química , Impresión TridimensionalRESUMEN
Blood urea nitrogen (BUN) to albumin ratio (BAR) is a comprehensive parameter that reflects renal, inflammatory, nutritional, and endothelial functions. BAR has been shown to be associated with various cancers, pneumonia, sepsis, and pulmonary and cardiovascular diseases; however, few studies have been conducted on its association with cerebrovascular diseases. In this study, we evaluated the association between BAR and cerebral small vessel disease (cSVD) in health check-up participants. We assessed consecutive health check-up participants between January 2006 and December 2013. For the cSVD subtype, we quantitatively measured the volume of white matter hyperintensity (WMH) and qualitatively measured the presence of lacune and cerebral microbleeds (CMBs). The BAR was calculated by dividing BUN by albumin as follows: BAR = BUN (mg/dl)/albumin (g/dl). A total of 3012 participants were evaluated. In multivariable linear regression analysis, BAR showed a statistically significant association with WMH volume after adjusting for confounders [ß = 0.076, 95% confidence interval (CI): 0.027-0.125]. In multivariable logistic regression analyses, BAR was significantly associated with lacunes [adjusted odds ratio (aOR) = 1.20, 95% CI: 1.00-1.44] and CMBs (aOR = 1.28, 95% CI: 1.06-1.55). BAR was associated with all types of cSVD in the health check-up participants.
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Enfermedades de los Pequeños Vasos Cerebrales , Imagen por Resonancia Magnética , Humanos , Nitrógeno de la Urea Sanguínea , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Albúmina Sérica/análisisRESUMEN
BACKGROUND: Inflammation is a major pathological mechanism underlying cerebrovascular disease. Recently, a new inflammatory marker based on the ratio between monocyte count and high-density lipoprotein (HDL) cholesterol has been proposed. In this study, we evaluated the relationship between monocyte-to-HDL cholesterol ratio (MHR) and cerebral small vessel disease (cSVD) lesions in health check-up participants. METHODS: This study was a retrospective cross-sectional study based on a registry that prospectively collected health check-up participants between 2006 and 2013. Three cSVD subtypes were measured on brain magnetic resonance imaging. White matter hyperintensity (WMH) volume, and lacunes and cerebral microbleeds (CMBs) were quantitatively and qualitatively measured, respectively. The MHR was calculated according to the following formula: MHR = monocyte counts (× 103/µL) / HDL cholesterol (mmol/L). RESULTS: In total, 3,144 participants were evaluated (mean age: 56 years, male sex: 53.9%). In multivariable analyzes adjusting for confounders, MHR was significantly associated with WMH volume [ß = 0.099, 95% confidence interval (CI) = 0.025 to 0.174], lacune [adjusted odds ratio (aOR) = 1.43, 95% CI = 1.07-1.91], and CMB (aOR = 1.51, 95% CI = 1.03-2.19). In addition, MHR showed a positive quantitative relationship with cSVD burden across all three subtypes: WMH (P < 0.001), lacunes (P < 0.001), and CMBs (P < 0.001). CONCLUSIONS: High MHR was closely associated with cSVD in health check-up participants. Because these associations appear across all cSVD subtypes, inflammation appears to be a major pathological mechanism in the development of various cSVDs.
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Enfermedades de los Pequeños Vasos Cerebrales , Monocitos , Humanos , Masculino , Persona de Mediana Edad , HDL-Colesterol , Estudios Retrospectivos , Estudios Transversales , Imagen por Resonancia Magnética , Inflamación/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/complicacionesRESUMEN
BACKGROUNDS AND OBJECTIVES: This study aimed to evaluate the applicability and precision of a ring-type cuffless blood pressure (BP) measurement device, CART-I Plus, compared to conventional 24-hour ambulatory BP monitoring (ABPM). METHODS: Forty patients were recruited, and 33 participants were included in the final analysis. Each participant wore both CART-I Plus and ABPM devices on the same arm for approximately 24 hours. BP estimation from CART-I Plus, derived from photoplethysmography (PPG) signals, were compared with the corresponding ABPM measurements. RESULTS: The CART-I Plus recorded systolic blood pressure (SBP)/diastolic blood pressure (DBP) values of 131.4±14.1/81.1±12.0, 132.7±13.9/81.9±11.9, and 128.7±14.6/79.3±12.2 mmHg for 24-hour, daytime, and nighttime periods respectively, compared to ABPM values of 129.7±11.7/84.4±11.2, 131.9±11.6/86.3±11.1, and 124.5±13.6/80.0±12.2 mmHg. Mean differences in SBP/DBP between the two devices were 1.74±6.69/-3.24±6.51 mmHg, 0.75±7.44/-4.41±7.42 mmHg, and 4.15±6.15/-0.67±5.23 mmHg for 24-hour, daytime, and nighttime periods respectively. Strong correlations were also observed between the devices, with r=0.725 and r=0.750 for transitions in SBP and DBP from daytime to nighttime, respectively (both p<0.001). CONCLUSIONS: The CART-I Plus device, with its unique ring-type design, shows promising accuracy in BP estimation and offers a potential avenue for continuous BP monitoring in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06084065.
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(1) Background: Adult spinal deformity (ASD) surgery is known to improve clinical and radiological parameters; however, it may also cause more complications in elderly patients. The purpose of this study was to compare the outcomes of ASD surgery, specifically regarding pain, disability, and health-related quality of life (HRQOL) in patients aged 75 years and over and patients aged under 75 years; (2) Methods: A total of 151 patients who underwent ASD surgery between August 2014 and September 2020 were included. Patients were divided into two groups based on whether they are 75 years and over or under. Radiological parameters measured included sagittal vertical axis (SVA), pelvic tilt (PT), and pelvic incidence (PI)- lumbar lordosis (LL). Data were collected 3, 6, and 12 months after surgery; (3) Results: At 12 months postoperatively, visual analog scale (VAS) for low back pain (p = 0.342), Oswestry disability index (ODI) (p = 0.087), and EuroQol 5-Dimensions (EQ-5D) (p = 0.125) did not differ between patients under 75 years and those 75 and above 75 group. PT (p = 0.675), PI-LL (p = 0.948), and SVA (p = 0.108) did not differ significantly 12 months after surgery in the two groups. In the entire patient group, compared to preoperative data, significant improvements were demonstrated for clinical and radiological parameters 12 months after surgery (all p < 0.001). The rate of medical complications did not correlate with age, but the rates of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) did (p = 0.638, p < 0.001, and p = 0.001, respectively); (4) Conclusions: In terms of clinical and radiological improvements, ASD surgery should be considered for patients regardless of whether they are younger than or older than 75 years. The clinical and radiological improvements and the risk of complications and revision surgeries must be considered in ASD patients who are 75 years or older.
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AIMS: As the process of bone regeneration is preceded by an inflammatory response, the immune system has long been considered important for fracture healing. Despite many studies on the contribution of immune cells to bone-related diseases, the role of immune cells in the regeneration therapy of lost bone is not well understood. In addition, various types of cells are involved in the clinical bone regeneration environment, but most of the osteo-biology studies are conducted in an osteoblast-only environment. MATERIALS AND METHODS: Here, we investigated the effects of macrophages and dendritic cells on osteogenic differentiation in a co-culture environment involving human periosteal cell-derived osteoblasts, human monocyte-derived osteoclasts, and myeloid-derived cells. In addition, the cluster of myeloid immune cells involved in the clinical bone regeneration process was analyzed through bone defect rat modeling. KEY FINDINGS: We found that specific types of myeloid cells and related cytokines increased osteogenic differentiation. These results were confirmed in experiments using myeloid cells originating from human primitive peripheral blood mononuclear cells and by measuring the colonization of macrophages and dendritic cells in an in vivo bone defect environment. In addition, Next generation sequencing (NGS) analysis was performed through RNA sequencing for osteogenesis caused by macrophages and dendritic cells in vitro, which implemented a clinical bone regeneration environment. The results of these experiments suggest that the role of M2 macrophages or dendritic cells is markedly increased during osteogenic differentiation. Therefore, we propose that the exchange of bioactive factors between macrophages and dendritic cells during the bone formation metabolic process is a crucial step of tissue regeneration rather than limited to the initial inflammatory response. SIGNIFICANCE: This study indicates that M2 macrophages, among myeloid cells, can be mediators that play a vital role in the effective bone regeneration process and shows the potential as a useful next-generation advanced cell therapy for bone regeneration treatment.
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Biomimética , Osteogénesis , Ratas , Humanos , Animales , Leucocitos Mononucleares , Regeneración Ósea , Macrófagos/metabolismo , Diferenciación CelularRESUMEN
Bone morphogenetic proteins (BMPs) have tremendous therapeutic potential regarding the treatment of bone and musculoskeletal disorders due to their osteo-inductive ability. More than twenty BMPs have been identified in the human body with various functions, such as embryonic development, skeleton genesis, hematopoiesis, and neurogenesis. BMPs can induce the differentiation of MSCs into the osteoblast lineage and promote the proliferation of osteoblasts and chondrocytes. BMP signaling is also involved in tissue remodeling and regeneration processes to maintain homeostasis in adults. In particular, growth factors, such as BMP-2 and BMP-7, have already been approved and are being used as treatments, but it is unclear as to whether they are the most potent BMPs that induce bone formation. According to recent studies, BMP-9 is known to be the most potent inducer of the osteogenic differentiation of mesenchymal stem cells, both in vitro and in vivo. However, its exact role in the skeletal system is still unclear. In addition, research results suggest that the molecular mechanism of BMP-9-mediated bone formation is also different from the previously known BMP family, suggesting that research on signaling pathways related to BMP-9-mediated bone formation is actively being conducted. In this study, we performed a phosphorylation array to investigate the signaling mechanism of BMP-9 compared with BMP-2, another influential bone-forming growth factor, and we compared the downstream signaling system. We present a mechanism for the signal transduction of BMP-9, focusing on the previously known pathway and the p53 factor, which is relatively upregulated compared with BMP-2.
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Factor 2 de Diferenciación de Crecimiento , Osteogénesis , Humanos , Proteína Morfogenética Ósea 2/farmacología , Proteína Morfogenética Ósea 2/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular , Factor 2 de Diferenciación de Crecimiento/metabolismo , Osteoblastos/metabolismo , Periostio/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Several significant associations between air pollution and thyroid function have been reported, but few studies have identified whether these associations differ by obesity, particularly its regional distribution. We assessed the relationship between ambient air pollution and thyroid hormone, and whether this relationship is modified by abdominal adiposity, as indicated by the waist circumference, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and visceral-to-subcutaneous fat ratio (VSR) in Korean men. METHODS: We included 2440 male adults in the final analysis and used each person's annual average exposure to four air pollutants: particulate matter with an aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide, sulfur dioxide (SO2), and carbon monoxide (CO). Abdominal fat deposition was quantified by computed tomography. Serum thyrotropin (TSH) and free thyroxine (FT4) concentrations were measured for thyroid hormone. To evaluate the relationship between air pollution and thyroid hormone according to adiposity, we performed multiple linear regression analysis on the two subgroups stratified by abdominal fat level. RESULTS: Abdominal adiposity was significantly related to FT4 concentration. The exposures to air pollutants were associated with increased TSH and decreased FT4 concentrations. In stratified analysis using abdominal fat traits, ambient air pollution except for SO2 was significantly related to increased TSH and decreased FT4 concentrations in the high adiposity group (all p < 0.05), but not in the normal adiposity group. Among the air pollutants, PM10 showed an association with an increase of TSH concentration in all group with high adiposity, including high VAT, high SAT, and high VSR groups (all p < 0.05). In case of FT4, CO showed a similar pattern. Among the abdominal fat-related traits, the VSR in the high adiposity group had the largest effect on the relationship between exposure to air pollutants and thyroid hormone. CONCLUSIONS: This study suggests the first clue that the relationship between air pollution exposure and thyroid hormone differs according to abdominal fat distribution among Korean adult males.
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Contaminantes Atmosféricos , Adulto , Humanos , Masculino , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Grasa Abdominal/diagnóstico por imagen , Obesidad , Hormonas Tiroideas/análisis , Tirotropina , República de Corea/epidemiologíaRESUMEN
Extrusion-based bioprinting technology is widely used for tissue regeneration and reconstruction. However, the method that uses only hydrogel as the bioink base material exhibits limited biofunctional properties and needs improvement to achieve the desired tissue regeneration. In this study, we present a three-dimensionally printed bioactive microparticle-loaded scaffold for use in bone regeneration applications. The unique structure of the microparticles provided sustained release of growth factor for > 4 weeks without the use of toxic or harmful substances. Before and after printing, the optimal particle ratio in the bioink for cell viability demonstrated a survival rate of ≥ 85% over 7 days. Notably, osteogenic differentiation and mineralization-mediated by human periosteum-derived cells in scaffolds with bioactive microparticles-increased over a 2-week interval. Here, we present an alternative bioprinting strategy that uses the sustained release of bioactive microparticles to improve biofunctional properties in a manner that is acceptable for clinical bone regeneration applications.
RESUMEN
Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.