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An electrochemical sensor based on an electroactive nanocomposite was designed for the first time consisting of electrochemically reduced graphene oxide (ERGO), polyaniline (PANI), and poly(alizarin red S) (PARS) for ciprofloxacin (CIPF) detection. The ERGO/PANI/PARS-modified screen-printed carbon electrode (SPCE) was constructed through a three-step electrochemical protocol and characterized using FTIR, UV-visible spectroscopy, FESEM, CV, LSV, and EIS. The new electrochemical CIPF sensor demonstrated a low detection limit of 0.0021 µM, a broad linear range of 0.01 to 69.8 µM, a high sensitivity of 5.09 µA/µM/cm2, and reasonable selectivity and reproducibility. Moreover, the ERGO/PANI/PARS/SPCE was successfully utilized to determine CIPF in milk with good recoveries and relative standard deviation (< 5%), which were close to those with HPLC analysis.
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Compuestos de Anilina , Antraquinonas , Carbono , Ciprofloxacina , Técnicas Electroquímicas , Electrodos , Grafito , Límite de Detección , Leche , Grafito/química , Leche/química , Compuestos de Anilina/química , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Animales , Ciprofloxacina/análisis , Carbono/química , Antraquinonas/química , Reproducibilidad de los Resultados , Contaminación de Alimentos/análisis , Antibacterianos/análisisRESUMEN
RAS proteins are peripheral membrane GTPases that activate multiple downstream effectors for cell proliferation and differentiation. The formation of a signaling RAS-RAF complex at the plasma membrane is implicated in a quarter of all human cancers; however, the underlying mechanism remains unclear. In this work, nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses to determine the structure of a hetero-tetrameric complex comprising KRAS and the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of activated RAF1 are employed. The binding of the RBD or RBD-CRD differentially alters the dimerization modes of KRAS on both anionic and neutral membranes, validated by interface-specific mutagenesis. Notably, the RBD binding allosterically generated two distinct KRAS dimer interfaces in equilibrium, favored by KRAS free and in complex with the RBD-CRD, respectively. Additional interactions of the CRD with both KRAS protomers are mutually cooperative to stabilize a new dimer configuration of KRAS bound to the RBD-CRD. The RAF binding sequentially alters KRAS dimerization, providing new insights into RAF activation, including a configurational transition of the KRAS dimer to provide an interaction site for the CRD and release the autoinhibited RAF complex. These methods are applicable to many other signaling protein complexes on the membrane.
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Bone-resorbing osteoclasts (OCLs) are formed by differentiation and fusion of monocyte precursor cells, generating large multi-nucleated cells. Tightly-regulated cell fusion during osteoclastogenesis leads to formation of resorption-competent OCLs, whose sizes fall within a predictable physiological range. The molecular mechanisms that regulate the onset of OCL fusion and its subsequent arrest are, however, largely unknown. We have previously shown that OCLs cultured from mice homozygous for the R51Q mutation in the vesicle trafficking-associated protein sorting nexin 10, a mutation that induces autosomal recessive osteopetrosis in humans and in mice, display deregulated and continuous fusion that generates gigantic, inactive OCLs. Fusion of mature OCLs is therefore arrested by an active, genetically-encoded, cell-autonomous, and SNX10-dependent mechanism. In order to directly examine whether SNX10 performs a similar role in vivo, we generated SNX10-deficient (SKO) mice and demonstrated that they display massive osteopetrosis and that their OCLs fuse uncontrollably in culture, as do homozygous R51Q SNX10 (RQ/RQ) mice. OCLs that lack SNX10 exhibit persistent presence of DC-STAMP protein at their periphery, which may contribute to their uncontrolled fusion. In order to visualize endogenous SNX10-mutant OCLs in their native bone environment we genetically labelled the OCLs of wild-type, SKO and RQ/RQ mice with EGFP, and then visualized the three-dimensional organization of resident OCLs and the pericellular bone matrix by two-photon, confocal, and second harmonics generation microscopy. We show that the volumes, surface areas and, in particular, the numbers of nuclei in the OCLs of both mutant strains were on average 2-6 fold larger than those of OCLs from wild-type mice, indicating that deregulated, excessive fusion occurs in the mutant mice. We conclude that the fusion of OCLs, and consequently their size, are regulated in vivo by SNX10-dependent arrest of fusion of mature OCLs.
Osteoclasts (OCLs) are cells that degrade bone. These cells are generated by fusion of monocyte precursor cells, but the mechanisms that regulate this process and eventually arrest it are unknown. We had previously shown that OCLs cultured from mice carrying the R51Q mutation in the protein sorting nexin 10 (SNX10) lose their resorptive capacity and become gigantic due to uncontrolled fusion. To examine whether SNX10 is required for OCL fusion arrest also in vivo, we inactivated the Snx10 gene in mice and fluorescently labelled their OCLs and OCLs of R51Q SNX10 mice, isolated their femurs, and used advanced 3D microscopy methods to visualize OCLs within the bone matrix. As expected, mice lacking SNX10 exhibited excessive bone mass, indicating that their OCLs are inactive. OCLs within bones of both mutant mouse strains were on average 2-6-fold larger than in control mice, and contained proportionally more nuclei. We conclude that OCL fusion is arrested in control, but not SNX10 mutant, mice, indicating that the sizes of mature OCLs are limited in vivo by an active, SNX10-dependent mechanism that suppresses cell fusion.
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Quantum dots (QDs) have garnered a significant amount of attention as promising memristive materials owing to their size-dependent tunable bandgap, structural stability, and high level of applicability for neuromorphic computing. Despite these advantageous properties, the development of QD-based memristors has been hindered by challenges in understanding and adjusting the resistive switching (RS) behavior of QDs. Herein, we propose three types of InP/ZnSe/ZnS QD-based memristors to elucidate the RS mechanism, employing a thin poly(methyl methacrylate) layer. This approach not only allows us to identify which carriers (electron or hole) are trapped within the QD layer but also successfully demonstrates QD-based synaptic devices. Furthermore, to utilize the QD memristor as a synapse, long-term potentiation/depression (LTP/LTD) characteristics are measured, resulting in a low nonlinearity of LTP/LTD at 0.1/1. On the basis of the LTP/LTD characteristics, single-layer perceptron simulations were performed using the Extended Modified National Institute of Standards and Technology, verifying a maximum recognition rate of 91.46%.
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Type II toxin-antitoxin (TA) systems are ubiquitously distributed genetic elements in prokaryotes and are crucial for cell maintenance and survival under environmental stresses. The antitoxin is a modular protein consisting of the disordered C-terminal region that physically contacts and neutralizes the cognate toxin and the well-folded N-terminal DNA binding domain responsible for autorepression of TA transcription. However, how the two functional domains communicate is largely unknown. Herein, we determined the crystal structure of the N-terminal domain of the type II antitoxin MazE-mt10 from Mycobacterium tuberculosis, revealing a homodimer of the ribbon-helix-helix (RHH) fold with distinct DNA binding specificity. NMR studies demonstrated that full-length MazE-mt10 forms the helical and coiled states in equilibrium within the C-terminal region, and that helical propensity is allosterically enhanced by the N-terminal binding to the cognate operator DNA. This coil-to-helix transition may promote toxin binding/neutralization of MazE-mt10 and further stabilize the TA-DNA transcription repressor. This is supported by many crystal structures of type II TA complexes in which antitoxins form an α-helical structure at the TA interface. The hidden helical state of free MazE-mt10 in solution, favored by DNA binding, adds a new dimension to the regulatory mechanism of type II TA systems. Furthermore, complementary approaches using X-ray crystallography and NMR allow us to study the allosteric interdomain interplay of many other full-length antitoxins of type II TA systems.
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Antitoxinas , Mycobacterium tuberculosis , Mycobacterium tuberculosis/metabolismo , Antitoxinas/química , Modelos Moleculares , Factores de Transcripción/metabolismo , ADN/metabolismo , Proteínas Bacterianas/metabolismoRESUMEN
The implications of administration of mRNA vaccines to individuals with chronic inflammatory diseases, including myocarditis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are unclear. We investigated mRNA vaccine effects in a chronic inflammation mouse model implanted with an LPS pump, focusing on toxicity and immunogenicity. Under chronic inflammation, mRNA vaccines exacerbated cardiac damage and myocarditis, inducing mild heart inflammation with heightened pro-inflammatory cytokine production and inflammatory cell infiltration in the heart. Concurrently, significant muscle damage occurred, with disturbances in mitochondrial fusion and fission factors signaling impaired muscle repair. However, chronic inflammation did not adversely affect muscles at the vaccination site or humoral immune responses; nevertheless, it partially reduced the cell-mediated immune response, particularly T-cell activation. These findings underscore the importance of addressing mRNA vaccine toxicity and immunogenicity in the context of chronic inflammation, ensuring their safe and effective utilization, particularly among vulnerable populations with immune-mediated inflammatory diseases.
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PURPOSE: Various vitrectomy probes are currently being used commercially, and there are ongoing efforts toward developing probes with higher cutting rates and smaller gauges. This study aimed to compare the efficiency and safety of various commercially available small gauge ultrahigh-speed dual pneumatic vitrectomy probes. METHODS: We retrospectively analyzed the medical records of patients and recorded intraoperative videos while they underwent microincision three-port vitrectomy surgery for idiopathic epiretinal membrane at Soonchunhyang University Seoul Hospital. The patients were categorized into four groups based on the vitrectomy probe used during surgery: 23-7500 (UltraVit 23-gauge 7,500 cuts per minute [CPM]), 23-7500 (UltraVit 25-gauge 7,500 CPM), 25-10K (Advanced UltraVit 25-gauge 10,000 CPM), and 27-10K (Advanced UltraVit 27-gauge 10,000 CPM). RESULTS: In total, 82 eyes from 82 patients were included in this work, with 16, 11, 26, and 29 eyes in groups 23-7500, 25-7500, 25-10K, and 27-10K, respectively. The corresponding vitrectomy times were 295.56 ± 53.55, 293.09 ± 50.28, 299.92 ± 59.42, and 349.38 ± 67.23 seconds, respectively. There was a significant difference in the vitrectomy time between the groups (p = 0.004). The mean number of sutures was 3, 3, 2.96, and 0.83, respectively. In the 23-7500 group, there was one case of iatrogenic retinal break, while in the 27-10K group, there was one case of postoperative hypotony. CONCLUSIONS: Although advancements have been made in the 27-gauge vitrectomy probe, it still takes more vitrectomy time than it does when using the 23- and 25-gauge probes. However, the delay was within an average of 1 minute, and considering the significantly reduced need for sutures, there is a substantial benefit in terms of postoperative discomfort. Therefore, when choosing a probe for epiretinal membrane surgery among the four options, it is reasonable to select the 27-gauge probe according to the surgeon's preference.
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Membrana Epirretinal , Perforaciones de la Retina , Humanos , Vitrectomía , Membrana Epirretinal/diagnóstico , Membrana Epirretinal/cirugía , Estudios Retrospectivos , Perforaciones de la Retina/diagnóstico , Perforaciones de la Retina/cirugía , Ojo , Complicaciones Posoperatorias/cirugíaRESUMEN
Self-assemblies (i.e., nanoclusters) of the RAS GTPase on the membrane act as scaffolds that activate downstream RAF kinases and drive MAPK signaling for cell proliferation and tumorigenesis. However, the mechanistic details of nanoclustering remain largely unknown. Here, size-tunable nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses revealed the structural basis of the cooperative assembly processes of fully processed KRAS, mutated in a quarter of human cancers. The cooperativity is modulated by the mutation and nucleotide states of KRAS and the lipid composition of the membrane. Notably, the oncogenic mutants assemble in nonsequential pathways with two mutually cooperative 'α/α' and 'α/ß' interfaces, while α/α dimerization of wild-type KRAS promotes the secondary α/ß interaction sequentially. Mutation-based interface engineering was used to selectively trap the oligomeric intermediates of KRAS and probe their favorable interface interactions. Transiently exposed interfaces were available for the assembly. Real-time NMR demonstrated that higher-order oligomers retain higher numbers of active GTP-bound protomers in KRAS GTPase cycling. These data provide a deeper understanding of the nanocluster-enhanced signaling in response to the environment. Furthermore, our methodology is applicable to assemblies of many other membrane GTPases and lipid nanoparticle-based formulations of stable protein oligomers with enhanced cooperativity.
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Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas ras/química , Quinasas raf/metabolismo , DimerizaciónRESUMEN
Cadaveric islet and stem cell-derived transplantations hold promise as treatments for type 1 diabetes. To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques have been developed that utilize diffusion to transport insulin across an immunoisolating barrier. However, despite several devices progressing to human clinical trials, none have successfully managed to attain physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with homeostatic, on-demand insulin delivery and physiologic glucose regulation, when reliant solely on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical proof and experimental validation that applying pressure at levels comparable to physiological diastolic blood pressure significantly enhances insulin flux across immunoisolation membranes-increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pump-based extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, effectively replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation. One Sentence Summary: Towards improved glucose control, applying sub-minute pressure at physiological levels enhances therapeutic insulin transport from macroencapsulated islets.
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The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.
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Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Animales , Ratones , Virus del Papiloma Humano , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/prevención & control , ARN Mensajero/genética , Proteínas E7 de Papillomavirus/genética , Ratones Endogámicos C57BL , Vacunación/métodos , Inmunización , Neoplasias del Cuello Uterino/prevención & controlRESUMEN
We developed a promising mRNA vaccine against severe fever with thrombocytopenia syndrome (SFTS), an infectious disease caused by the SFTS virus that is primarily transmitted through tick bites. Administration of lipid nanoparticle-encapsulated mRNA-Gn successfully induced neutralizing antibodies and T-cell responses in mice. The vaccinated mice were protected against a lethal SFTS virus challenge, suggesting that this mRNA vaccine may be an effective and successful SFTS vaccine candidate.
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We propose that the post-deposition oxidation of the IGZO surface is essential for improving the interface quality, with Al2O3 prepared by atomic layer deposition (ALD) employing a common metal precursor trimethylaluminum (TMA). Here, the ALD-Al2O3 process was conducted using H2O as an oxidant at a substrate temperature of 150 °C after IGZO deposition. The depth-resolved X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) data reveal the defect-rich and poor interface of the standard Al2O3/IGZO stack due to the redox reaction between the IGZO surface and TMA. The anion character of the IGZO was modified by introducing fluorine, which is known as a stability enhancer for oxide semiconductors. We highlight that the presence of the fluorine also improves the interface quality with ALD-Al2O3. As a consequence of the fluorine incorporation prior to the ALD-Al2O3 process, the chemical reduction reaction of the IGZO surface was effectively alleviated, resulting in a defect-passivated and sharp interface owing to the strong oxidizing nature of the fluorine.
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Introduction: Since the Coronavirus disease 2019 (COVID-19), public safety measures, including social distancing and school closures, have been implemented, precipitating psychological difficulties and heightened online activities for adolescents. However, studies examining the impact of the pandemic on adolescent mental health and their coping strategies in Asian countries are limited. Further, most studies have used survey measures to capture mental health challenges so far. Accordingly, this study aimed to examine the psychological challenges South Korean adolescents experienced and their coping strategies during the pandemic using the Natural Language Processing (NLP) and Text mining (TM) technique on adolescents' social media texts/posts. Methods: The data were gathered from social media texts/posts such as online communities, Twitter, and personal blogs from January 1, 2019, to October 31, 2021. The 12,520,250 texts containing keywords related to adolescents' common psychological difficulties reported during the pandemic, including self-harm, Attention-Deficit/Hyperactivity Disorders (ADHD), and insomnia, were analyzed by TM, NLP using information extraction, co-occurrence and sentiment analysis. The monthly frequency of the keywords and their associated words was also analyzed to understand the time trend. Results: Adolescents used the word "self-harm" in their social media texts more frequently during the second wave of COVID-19 (August to September 2020). "Friends" was the most associated word with "self-harm." While the frequency of texts with "Insomnia" stayed constant throughout the pandemic, the word "ADHD" was increasingly mentioned in social media. ADHD and insomnia were most frequently associated with ADHD medications and sleeping pills, respectively. Friends were generally associated with positive words, while parents were associated with negative words. Conclusion: During COVID-19, Korean adolescents often expressed their psychological challenges on social media platforms. However, their coping strategies seemed less efficient to help with their difficulties, warranting strategies to support them in the prolonged pandemic era. For example, Korean adolescents shared psychological challenges such as self-harm with friends rather than their parents. They considered using medicine (e.g., sleeping pills and ADHD medication) as coping strategies for sleep and attention problems.
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The highly pathogenic avian influenza (HPAI) virus triggers infectious diseases, resulting in pulmonary damage and high mortality in domestic poultry worldwide. This study aimed to analyze miRNA expression profiles after infection with the HPAI H5N1 virus in resistant and susceptible lines of Ri chickens.For this purpose, resistant and susceptible lines of Vietnamese Ri chicken were used based on the A/G allele of Mx and BF2 genes. These genes are responsible for innate antiviral activity and were selected to determine differentially expressed (DE) miRNAs in HPAI-infected chicken lines using small RNA sequencing. A total of 44 miRNAs were DE after 3 days of infection with the H5N1 virus. Computational program analysis indicated the candidate target genes for DE miRNAs to possess significant functions related to cytokines, chemokines, MAPK signaling pathway, ErBb signaling pathway, and Wnt signaling pathway. Several DE miRNA-mRNA matches were suggested to play crucial roles in mediating immune functions against viral evasion. These results revealed the potential regulatory roles of miRNAs in the immune response of the two Ri chicken lines against HPAI H5N1 virus infection in the lungs.
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Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.
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Adipocitos , Osteogénesis , Animales , Ratones , Osteogénesis/genética , Adiposidad , Envejecimiento/genética , Artrodesis , Ratones Noqueados , Agitación PsicomotoraRESUMEN
BACKGROUND: Pacemakers assist circulation by generating electrical impulses. Patients with pacemakers scheduled to undergo surgery are vulnerable to device-related complications. Therefore, careful perioperative management is required to prevent undesirable events. CASE: A 66-year-old man with alcohol-related hepatocellular carcinoma was referred for liver transplantation. The pacemaker was inserted preoperatively to manage sick sinus syndrome and paroxysmal atrial fibrillation. Overall liver transplantation was performed without any adverse events. However, the pacemaker suddenly failed to provide regular pacing rhythm during abdominal closure. Fortunately, the native heart rate was maintained above 70 beats per minute and blood pressure did not fluctuate after pacing failure. After retrospective analysis, the duration setting of preoperative pacemaker reprogramming (24 h) was revealed as the cause of unexpected pacing failure. CONCLUSIONS: Anesthesiologists should be alert in patients with pacemakers because minor errors may lead to inadvertent failure of pacing or severe hemodynamic instability.
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PURPOSE: To compare and analyze the performance of dual pneumatic ultra-high-speed vitreous cutters based on their cut rates, vacuum levels, and diameters in terms of flow rate and cutting time. METHODS: The Constellation Vision System was used to remove egg white for 30 seconds, after which we calculated the flow rate by measuring the change in weight. We then measured the time required to remove 4 mL of egg white. We tested the UltraVit (UV) 7,500 cuts per minute (cpm) probe and the Advanced UltraVit (AUV) 10,000 cpm probe in biased open duty cycle mode, using 23-, 25-, and 27-gauge probes, respectively. RESULTS: In biased open duty cycle, the flow rate tended to decrease as the cut rates increased for all three gauges. At the same cut rates, the flow rate increased as the vacuum level increased (p < 0.05), and as the diameter increased (p < 0.05). Among cutters with the same diameter, the AUV cutter showed higher flow rates than the UV cutter, with increases of 0.267 mL/min (18.5%) at 27 gauge, 0.627 mL/min (20.8%) at 25 gauge, and 1.000 mL/min (20.7%) at 23 gauge (all p < 0.05). The times required to remove 4 mL of egg white took longer with the UV cutter than the AUV cutter for all three gauges (all p < 0.05). CONCLUSIONS: The use of a smaller gauge vitreous cutter may reduce the flow rate and increase the time required for vitrectomy, but this can be partially compensated for by increasing the vacuum level as well as using a vitreous cutter with a higher maximum cut rate, improved port size, and improved duty cycle.
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Vitrectomía , Cuerpo Vítreo , Humanos , Cuerpo Vítreo/cirugía , MicrocirugiaRESUMEN
Despite various intraoperative thermal strategies, core heat loss is considerable during liver transplantation and hypothermia is common. We tested whether forced-air prewarming prevents hypothermia during liver transplantation. Adult patients undergoing living donor liver transplantation were randomly assigned to non-prewarming group (n = 20) or prewarming group (n = 20). Patients in prewarming group underwent 30-min forced-air warming before anesthetic induction. During surgery, core temperature was measured in the pulmonary artery. The primary outcome was intraoperative hypothermia (< 36.0 °C). The secondary outcomes included plasma lactate concentration. Intraoperative hypothermia risk was significantly lower in prewarming group than in non-prewarming group (60.0% vs. 95.0%, P = 0.020). The difference in hypothermia incidence between groups was greater in the post-induction phase (20.0% vs. 85.0%, P < 0.001) than in the anhepatic or post-reperfusion phase, suggesting that prewarming mainly acts on preventing post-induction core-to-peripheral heat redistribution. Hypothermia duration was significantly shorter in prewarming group (60 [0-221] min vs. 383 [108-426] min, P = 0.001). Lactate concentration decreased during 3 h after graft reperfusion in prewarming group, whereas it continuously increased in non-prewarming group (- 0.19 [- 0.48 to 0.13] mmol/L vs. 1.17 [3.31-0.77] mmol/L, P = 0.034). In conclusion, forced-air prewarming decreases the incidence and duration of intraoperative hypothermia with potential clinical benefit while mainly acting by preventing the core-to-peripheral heat redistribution.Clinical trial registration: Registered at the Clinical Research Information Service ( https://cris.nih.go.kr , [KCT0003230]) on 01/10/2018.
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Hipotermia , Trasplante de Hígado , Adulto , Humanos , Hipotermia/prevención & control , Hipotermia/etiología , Trasplante de Hígado/efectos adversos , Donadores Vivos , Regulación de la Temperatura Corporal , Calor , Temperatura CorporalRESUMEN
Periosteal stem and progenitor cells (PSPCs) are major contributors to bone maintenance and repair. Deciphering the molecular mechanisms that regulate their function is crucial for the successful generation and application of future therapeutics. Here, we pinpoint Hox transcription factors as necessary and sufficient for periosteal stem cell function. Hox genes are transcriptionally enriched in periosteal stem cells and their overexpression in more committed progenitors drives reprogramming to a naïve, self-renewing stem cell-like state. Crucially, individual Hox family members are expressed in a location-specific manner and their stem cell-promoting activity is only observed when the Hox gene is matched to the anatomical origin of the PSPC, demonstrating a role for the embryonic Hox code in adult stem cells. Finally, we demonstrate that Hoxa10 overexpression partially restores the age-related decline in fracture repair. Together, our data highlight the importance of Hox genes as key regulators of PSPC identity in skeletal homeostasis and repair.
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Células Madre Adultas , Genes Homeobox , Humanos , Adulto , Genes Homeobox/genética , Proteínas de Homeodominio/genética , Células Madre , HuesosRESUMEN
Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.