RESUMO
Excessive precipitation over the southeastern tropical Pacific is a major common bias that persists through generations of global climate models. While recent studies suggest an overly warm Southern Ocean as the cause, models disagree on the quantitative importance of this remote mechanism in light of ocean circulation feedback. Here, using a multimodel experiment in which the Southern Ocean is radiatively cooled, we show a teleconnection from the Southern Ocean to the tropical Pacific that is mediated by a shortwave subtropical cloud feedback. Cooling the Southern Ocean preferentially cools the southeastern tropical Pacific, thereby shifting the eastern tropical Pacific rainbelt northward with the reduced precipitation bias. Regional cloud locking experiments confirm that the teleconnection efficiency depends on subtropical stratocumulus cloud feedback. This subtropical cloud feedback is too weak in most climate models, suggesting that teleconnections from the Southern Ocean to the tropical Pacific are stronger than widely thought.
Assuntos
Modelos Teóricos , Oceanos e Mares , Clima Tropical , Oceano Pacífico , TemperaturaRESUMO
A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.
Assuntos
Carboxipeptidases , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Camundongos , Diferenciação Celular/fisiologia , Carboxipeptidases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Osteogênese , Osteoblastos/metabolismo , FosforilaçãoRESUMO
Job syndrome is a rare genetic disorder caused by STAT3 mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, Stat3 loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that Stat3 loss resulted in down-regulation of Wnt/ß-catenin signaling. Restoration of Wnt/ß-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 in maintaining Wnt/ß-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/ß-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/ß-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.
Assuntos
Osso e Ossos/patologia , Síndrome de Job/metabolismo , Síndrome de Job/patologia , Células-Tronco Mesenquimais/metabolismo , Fator de Transcrição STAT3/deficiência , Via de Sinalização Wnt , Alelos , Animais , Cartilagem/patologia , Diferenciação Celular , Embrião de Mamíferos/patologia , Extremidades/patologia , Deleção de Genes , Humanos , Integrases/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Células-Tronco Mesenquimais/patologia , Mesoderma/embriologia , Camundongos Transgênicos , Osteoblastos/patologia , OsteogêneseRESUMO
Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporated doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX was expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results showed that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX were injectable and had a 2-fold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels showed sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells showed MMP inhibition (ca. an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occluded a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.
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The human brain and central nervous system (CNS) present unique challenges in drug development for neurological diseases. One major obstacle is the blood-brain barrier (BBB), which hampers the effective delivery of therapeutic molecules into the brain while protecting it from blood-born neurotoxic substances and maintaining CNS homeostasis. For BBB research, traditional in vitro models rely upon Petri dishes or Transwell systems. However, these static models lack essential microenvironmental factors such as shear stress and proper cell-cell interactions. To this end, organ-on-a-chip (OoC) technology has emerged as a new in vitro modeling approach to better recapitulate the highly dynamic in vivo human brain microenvironment so-called the neural vascular unit (NVU). Such BBB-on-a-chip models have made substantial progress over the last decade, and concurrently there has been increasing interest in modeling various neurological diseases such as Alzheimer's disease and Parkinson's disease using OoC technology. In addition, with recent advances in other scientific technologies, several new opportunities to improve the BBB-on-a-chip platform via multidisciplinary approaches are available. In this review, an overview of the NVU and OoC technology is provided, recent progress and applications of BBB-on-a-chip for personalized medicine and drug discovery are discussed, and current challenges and future directions are delineated.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Transporte Biológico , Encéfalo , Humanos , Dispositivos Lab-On-A-ChipRESUMO
Silk fibroin (SF) is a promising biomaterial for tendon repair, but its relatively rigid mechanical properties and low cell affinity have limited its application in regenerative medicine. Meanwhile, gelatin-based polymers have advantages in cell attachment and tissue remodeling but have insufficient mechanical strength to regenerate tough tissue such as tendons. Taking these aspects into account, in this study, gelatin methacryloyl (GelMA) is combined with SF to create a mechanically strong and bioactive nanofibrous scaffold (SG). The mechanical properties of SG nanofibers can be flexibly modulated by varying the ratio of SF and GelMA. Compared to SF nanofibers, mesenchymal stem cells (MSCs) seeded on SG fibers with optimal composition (SG7) exhibit enhanced growth, proliferation, vascular endothelial growth factor production, and tenogenic gene expression behavior. Conditioned media from MSCs cultured on SG7 scaffolds can greatly promote the migration and proliferation of tenocytes. Histological analysis and tenogenesis-related immunofluorescence staining indicate SG7 scaffolds demonstrate enhanced in vivo tendon tissue regeneration compared to other groups. Therefore, rational combinations of SF and GelMA hybrid nanofibers may help to improve therapeutic outcomes and address the challenges of tissue-engineered scaffolds for tendon regeneration.
Assuntos
Fibroínas , Células-Tronco Mesenquimais , Nanofibras , Proliferação de Células , Gelatina , Células-Tronco Mesenquimais/metabolismo , Metacrilatos , Seda , Tendões , Engenharia Tecidual , Alicerces Teciduais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)Cdh1 E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in Drosophila eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/CCdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.
Assuntos
Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Proteínas Cdh1/metabolismo , Proteínas de Drosophila/metabolismo , Fase G1/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Ciclossomo-Complexo Promotor de Anáfase/genética , Animais , Antígenos CD/genética , Caderinas/genética , Proteínas Cdh1/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Células HEK293 , Células HeLa , Via de Sinalização Hippo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Despite considerable efforts in modeling liver disease in vitro, it remains difficult to recapitulate the pathogenesis of the advanced phases of non-alcoholic fatty liver disease (NAFLD) with inflammation and fibrosis. Here, a liver-on-a-chip platform with bioengineered multicellular liver microtissues is developed, composed of four major types of liver cells (hepatocytes, endothelial cells, Kupffer cells, and stellate cells) to implement a human hepatic fibrosis model driven by NAFLD: i) lipid accumulation in hepatocytes (steatosis), ii) neovascularization by endothelial cells, iii) inflammation by activated Kupffer cells (steatohepatitis), and iv) extracellular matrix deposition by activated stellate cells (fibrosis). In this model, the presence of stellate cells in the liver-on-a-chip model with fat supplementation showed elevated inflammatory responses and fibrosis marker up-regulation. Compared to transforming growth factor-beta-induced hepatic fibrosis models, this model includes the native pathological and chronological steps of NAFLD which shows i) higher fibrotic phenotypes, ii) increased expression of fibrosis markers, and iii) efficient drug transport and metabolism. Taken together, the proposed platform will enable a better understanding of the mechanisms underlying fibrosis progression in NAFLD as well as the identification of new drugs for the different stages of NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Células Endoteliais , Hepatócitos , Humanos , Fígado/patologia , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID-19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost-effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip-based integrated platforms, and nano- and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip-based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted.
Assuntos
COVID-19 , Viroses , Humanos , Nanotecnologia , Pandemias , SARS-CoV-2 , Viroses/diagnósticoRESUMO
Cancer immunotherapies, including immune checkpoint inhibitor (ICI)-based therapies, have revolutionized cancer treatment. However, patient response to ICIs is highly variable, necessitating the development of methods to quickly assess efficacy. In this study, an array of miniaturized bioreactors has been developed to model tumor-immune interactions. This immunotherapeutic high-throughput observation chamber (iHOC) is designed to test the effect of anti-PD-1 antibodies on cancer spheroid (MDA-MB-231, PD-L1+) and T cell (Jurkat) interactions. This system facilitates facile monitoring of T cell inhibition and reactivation using metrics such as tumor infiltration and interleukin-2 (IL-2) secretion. Status of the tumor-immune interactions can be easily captured within the iHOC by measuring IL-2 concentration using a micropillar array where sensitive, quantitative detection is allowed after antibody coating on the surface of array. The iHOC is a platform that can be used to model and monitor cancer-immune interactions in response to immunotherapy in a high-throughput manner.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Imunoterapia , Dispositivos Lab-On-A-Chip , Neoplasias/tratamento farmacológicoRESUMO
PURPOSE: To compare the performance of a dual-lumen flushable drainage catheter to a conventional catheter for complex fluid collection drainage. METHODS: Two prototype catheters (20- and 28-F) were created by incorporating a customized infusion lumen within the wall of a large-bore conventional drainage catheter, which facilitated simultaneous irrigation of the drainage lumen and the targeted collection via inward- and outward-facing infusion side holes. These were tested against unaltered 20- and 28-F conventional catheters to determine if the injection of a dedicated flush lumen improved rapidity and completeness of gravity drainage. In vitro models were created to simulate serous fluid, purulent/exudative fluid, particulate debris, and acute hematoma. RESULTS: In the purulent model, mean drainage rate was 19.9 ± 8.0 and 9.5±1.4 mL/min for the 20-F prototype and control (P < .001) and 63.9 ± 4.3 and 35.4 ± 3.4 mL/min for the 28-F prototype and control (P = .006), respectively, with complete drainage achieved in all trials. In the particulate model, mean drainage rate was 24.5 ± 9.7 and 12.0 ± 12.5 mL/min for the 28-F prototype and control (P = .003), respectively, with 69.0% versus 41.1% total drainage achieved over 24 minutes (P = .029). In the hematoma model, mean drainage rate was 22.7 ± 4.6 and 4.8 ± 4.3 mL/min for the 28-F prototype and control (P = .022), respectively, with 80.3% versus 20.1% drainage achieved over 15 minutes (P = .003). Particulate and hematoma 20-F prototypes and conventional trials failed due to immediate occlusion. CONCLUSIONS: The proposed dual-lumen drainage catheter with irrigation of a dedicated flush lumen improved evacuation of complex fluid collections in vitro.
Assuntos
Cateterismo/instrumentação , Catéteres , Drenagem/instrumentação , Irrigação Terapêutica/instrumentação , Desenho de Equipamento , Teste de Materiais , Fatores de TempoRESUMO
BACKGROUND: Two deep-sea eels collected from the Western Pacific Ocean are described in this study. Based on their morphological characteristics, the two deep-sea eel specimens were assumed to belong to the cusk-eel family Ophidiidae and the cutthroat eel family Synaphobranchidae. METHODS AND RESULTS: To accurately identify the species of the deep-sea eel specimens, we sequenced the mitochondrial genes (cytochrome c oxidase subunit I [COI] and 16S ribosomal RNA [16S rRNA]). Through molecular phylogenetic analysis based on mtDNA COI and 16S rRNA gene sequences, these species clustered with the genera Bassozetus and Synaphobranchus, suggesting that the deep-sea eel specimens collected are two species from the genera Bassozetus and Synaphobranchus in the Western Pacific Ocean, respectively. CONCLUSIONS: This is the first study to report new records of the genera Bassozetus and Synaphobranchus from the Western Pacific Ocean based on COI and 16S rRNA genes.
Assuntos
Enguias/classificação , Enguias/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , RNA Ribossômico 16S/genética , Animais , Geografia , Sequenciamento de Nucleotídeos em Larga Escala , Oceano Pacífico , Fenótipo , FilogeniaRESUMO
BACKGROUND: Increasing antibiotic resistance continues to focus on research into the discovery of novel antimicrobial agents. Due to its antimicrobial and wound healing-promoting activity, metal nanoparticles have attracted attention for dermatological applications. This study is designed to investigate the scope and bactericidal potential of zinc ferrite nanoparticles (ZnFe2O4 NPs), and the mechanism of anti-bacterial action along with cytocompatibility, hemocompatibility, and wound healing properties. RESULTS: ZnFe2O4 NPs were synthesized via a modified co-precipitation method. Structure, size, morphology, and elemental compositions of ZnFe2O4 NPs were analyzed using X-ray diffraction pattern, Fourier transform infrared spectroscopy, and field emission scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy. In PrestoBlue and live/dead assays, ZnFe2O4 NPs exhibited dose-dependent cytotoxic effects on human dermal fibroblasts. In addition, the hemocompatibility assay revealed that the NPs do not significantly rupture red blood cells up to a dose of 1000 µg/mL. Bacterial live/dead imaging and zone of inhibition analysis demonstrated that ZnFe2O4 NPs showed dose-dependent bactericidal activities in various strains of Gram-negative and Gram-positive bacteria. Interestingly, NPs showed antimicrobial activity through multiple mechanisms, such as cell membrane damage, protein leakage, and reactive oxygen species generation, and were more effective against gram-positive bacteria. Furthermore, in vitro scratch assay revealed that ZnFe2O4 NPs improved cell migration and proliferation of cells, with noticeable shrinkage of the artificial wound model. CONCLUSIONS: This study indicated that ZnFe2O4 NPs have the potential to be used as a future antimicrobial and wound healing drug.
Assuntos
Antibacterianos/farmacologia , Compostos Férricos/farmacologia , Nanopartículas , Cicatrização/efeitos dos fármacos , Zinco/farmacologia , Animais , Antibacterianos/química , Linhagem Celular , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/tratamento farmacológico , Compostos Férricos/química , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/ultraestrutura , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Zinco/químicaRESUMO
Mesenchymal stem cells (MSCs) have been widely used for regenerative therapy. In most current clinical applications, MSCs are delivered by injection but face significant issues with cell viability and penetration into the target tissue due to a limited migration capacity. Some therapies have attempted to improve MSC stability by their encapsulation within biomaterials; however, these treatments still require an enormous number of cells to achieve therapeutic efficacy due to low efficiency. Additionally, while local injection allows for targeted delivery, injections with conventional syringes are highly invasive. Due to the challenges associated with stem cell delivery, a local and minimally invasive approach with high efficiency and improved cell viability is highly desired. In this study, we present a detachable hybrid microneedle depot (d-HMND) for cell delivery. Our system consists of an array of microneedles with an outer poly(lactic-co-glycolic) acid (PLGA) shell and an internal gelatin methacryloyl (GelMA)-MSC mixture (GMM). The GMM was characterized and optimized for cell viability and mechanical strength of the d-HMND required to penetrate mouse skin tissue was also determined. MSC viability and function within the d-HMND was characterized in vitro and the regenerative efficacy of the d-HMND was demonstrated in vivo using a mouse skin wound model.
RESUMO
Gelatin methacryloyl (GelMA) is a widely used hydrogel with skin-derived gelatin acting as the main constituent. However, GelMA has not been used in the development of wearable biosensors, which are emerging devices that enable personalized healthcare monitoring. This work highlights the potential of GelMA for wearable biosensing applications by demonstrating a fully solution-processable and transparent capacitive tactile sensor with microstructured GelMA as the core dielectric layer. A robust chemical bonding and a reliable encapsulation approach are introduced to overcome detachment and water-evaporation issues in hydrogel biosensors. The resultant GelMA tactile sensor shows a high-pressure sensitivity of 0.19 kPa-1 and one order of magnitude lower limit of detection (0.1 Pa) compared to previous hydrogel pressure sensors owing to its excellent mechanical and electrical properties (dielectric constant). Furthermore, it shows durability up to 3000 test cycles because of tough chemical bonding, and long-term stability of 3 days due to the inclusion of an encapsulation layer, which prevents water evaporation (80% water content). Successful monitoring of various human physiological and motion signals demonstrates the potential of these GelMA tactile sensors for wearable biosensing applications.
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Stem cells secrete trophic factors that induce angiogenesis. These soluble factors are promising candidates for stem cell-based therapies, especially for cardiovascular diseases. Mechanical stimuli and biophysical factors presented in the stem cell microenvironment play important roles in guiding their behaviors. However, the complex interplay and precise role of these cues in directing pro-angiogenic signaling remain unclear. Here, a platform is designed using gelatin methacryloyl hydrogels with tunable rigidity and a dynamic mechanical compression bioreactor to evaluate the influence of matrix rigidity and mechanical stimuli on the secretion of pro-angiogenic factors from human mesenchymal stem cells (hMSCs). Cells cultured in matrices mimicking mechanical elasticity of bone tissues in vivo show elevated secretion of vascular endothelial growth factor (VEGF), one of representative signaling proteins promoting angiogenesis, as well as increased vascularization of human umbilical vein endothelial cells (HUVECs) with a supplement of conditioned media from hMSCs cultured across different conditions. When hMSCs are cultured in matrices stimulated with a range of cyclic compressions, increased VEGF secretion is observed with increasing mechanical strains, which is also in line with the enhanced tubulogenesis of HUVECs. Moreover, it is demonstrated that matrix stiffness and cyclic compression modulate secretion of pro-angiogenic molecules from hMSCs through yes-associated protein activity.
Assuntos
Células-Tronco Mesenquimais , Células Cultivadas , Sinais (Psicologia) , Meios de Cultivo Condicionados , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio VascularRESUMO
The extraction of interstitial fluid (ISF) from skin using microneedles (MNs) has attracted growing interest in recent years due to its potential for minimally invasive diagnostics and biosensors. ISF collection by absorption into a hydrogel MN patch is a promising way that requires the materials to have outstanding swelling ability. Here, a gelatin methacryloyl (GelMA) patch is developed with an 11 × 11 array of MNs for minimally invasive sampling of ISF. The properties of the patch can be tuned by altering the concentration of the GelMA prepolymer and the crosslinking time; patches are created with swelling ratios between 293% and 423% and compressive moduli between 3.34 MPa and 7.23 MPa. The optimized GelMA MN patch demonstrates efficient extraction of ISF. Furthermore, it efficiently and quantitatively detects glucose and vancomycin in ISF in an in vivo study. This minimally invasive approach of extracting ISF with a GelMA MN patch has the potential to complement blood sampling for the monitoring of target molecules from patients.
Assuntos
Líquido Extracelular , Gelatina , Hidrogéis , Agulhas/classificação , Pele , HumanosRESUMO
Thrombosis is a life-threatening pathological condition in which blood clots form in blood vessels, obstructing or interfering with blood flow. Thrombolytic agents (TAs) are enzymes that can catalyze the conversion of plasminogen to plasmin to dissolve blood clots. The plasmin formed by TAs breaks down fibrin clots into soluble fibrin that finally dissolves thrombi. Several TAs have been developed to treat various thromboembolic diseases, such as pulmonary embolisms, acute myocardial infarction, deep vein thrombosis, and extensive coronary emboli. However, systemic TA administration can trigger non-specific activation that can increase the incidence of bleeding. Moreover, protein-based TAs are rapidly inactivated upon injection resulting in the need for large doses. To overcome these limitations, various types of nanocarriers have been introduced that enhance the pharmacokinetic effects by protecting the TA from the biological environment and targeting the release into coagulation. The nanocarriers show increasing half-life, reducing side effects, and improving overall TA efficacy. In this work, the recent advances in various types of TAs and nanocarriers are thoroughly reviewed. Various types of nanocarriers, including lipid-based, polymer-based, and metal-based nanoparticles are described, for the targeted delivery of TAs. This work also provides insights into issues related to the future of TA development and successful clinical translation.
Assuntos
Infarto do Miocárdio , Trombose , Coagulação Sanguínea , Preparações de Ação Retardada/uso terapêutico , Fibrinolíticos/uso terapêutico , Humanos , Trombose/tratamento farmacológicoRESUMO
Hippo signaling controls organ size by regulating cell proliferation and apoptosis. Yes-associated protein (YAP) is a key downstream effector of Hippo signaling, and LATS-mediated phosphorylation of YAP at Ser127 inhibits its nuclear localization and transcriptional activity. Here, we report that Nemo-like kinase (NLK) phosphorylates YAP at Ser128 both in vitro and in vivo, which blocks interaction with 14-3-3 and enhances its nuclear localization. Depletion of NLK increases YAP phosphorylation at Ser127 and reduces YAP-mediated reporter activity. These results suggest that YAP phosphorylation at Ser128 and at Ser127 may be mutually exclusive. We also find that with the increase in cell density, nuclear localization and the level of NLK are reduced, resulting in reduction in YAP phosphorylation at Ser128. Furthermore, knockdown of Nemo (the Drosophila NLK) in fruit fly wing imaginal discs results in reduced expression of the Yorkie (the Drosophila YAP) target genes expanded and DIAP1, while Nemo overexpression reciprocally increased the expression. Overall, our data suggest that NLK/Nemo acts as an endogenous regulator of Hippo signaling by controlling nuclear localization and activity of YAP/Yorkie.
Assuntos
Proteínas 14-3-3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Contagem de Células , Proteínas de Ciclo Celular , Linhagem Celular , Movimento Celular , Núcleo Celular/metabolismo , Drosophila , Humanos , Camundongos , Proteínas Nucleares/química , Fosforilação , Ligação Proteica , Transporte Proteico , Serina/química , Serina/metabolismo , Fatores de Transcrição/química , Transcrição GênicaRESUMO
A novel and an efficient rescue system with a multi-agent simultaneous localization and mapping (SLAM) framework is proposed to reduce the rescue time while rescuing the people trapped inside a burning building. In this study, the truncated signed distance (TSD) based SLAM algorithm is employed to accurately construct a two-dimensional map of the surroundings. For a new and significantly different scenario, information is gathered and the general iterative closest point method (GICP) is directly employed instead of the conventional TSD-SLAM process. Rescuers can utilize a total map created by merging individual maps, allowing them to efficiently search for victims. For online map merging, it is essential to determine the timing of when the individual maps are merged and the extent to which one map reflects the other map, via the weights. In the several experiments conducted, a light-detection and ranging system and an inertial measurement unit were integrated into a smart helmet for rescuers. The results indicated that the map was built more accurately than that obtained using the conventional TSD-SLAM. Additionally, the merged map was built more correctly by determining proper parameters for online map merging. Consequently, the accurate merged map allows rescuers to search for victims efficiently.