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Due to the continuous rise in global incidence and severity of invasive fungal infections (IFIs), particularly among immunocompromised and immunodeficient patients, there is an urgent demand for swift and accurate fungal pathogen diagnosis. Therefore, the need for fungal-specific positron emission tomography (PET) imaging agents that can detect the infection in the early stages is increasing. Cellobiose, a disaccharide, is readily metabolized by fungal pathogens such as Aspergillus species. Recently, our group reported fluorine-18 labeled cellobiose, 2-deoxy-2-[18F]fluorocellobiose ([18F]FCB), for specific imaging of Aspergillus infection. The positive imaging findings with very low background signal on delayed imaging make this ligand a promising fungal-specific imaging ligand. Inspired by this result, the decision was made to automate the radiolabeling procedure for better reproducibility and to facilitate clinical translation. A Trasis AllInOne (Trasis AIO) automated module was used for this purpose. The reagent vials contain commercially available 2-deoxy-2-[18F]fluoroglucose ([18F]FDG), glucose-1-phosphate, and enzyme (cellobiose phosphorylase). A Sep-Pak cartridge was used to purify the tracer. The overall radiochemical yield was 50%-70% (n = 6, decay corrected) in 75-min synthesis time with a radiochemical purity of > 98%. This is a highly reliable protocol to produce current good manufacturing practice (cGMP)-compliant [18F]FCB for clinical PET imaging.
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Celobiose , Celobiose/síntese química , Celobiose/química , Celobiose/análogos & derivados , Técnicas de Química Sintética , Automação , RadioquímicaRESUMO
Loess areas, such as the Loess Plateau, are characterized by a fragile ecological environment, high soil erosion, and frequent geological disasters due to the unique hydrological properties of loess (e.g., collapsibility and permeability). Therefore, the loess must be stabilized for use in engineering construction. Traditional stabilizers (lime, cement, and fly ash) cause environmental problems, such as soil salinization and greenhouse gas emissions. Therefore, this study investigated the effect of nanosilica on the hydrological properties of loess and the microscopic mechanism. Different nanosilica contents (0.2%, 0.4%, 0.8%, 1%, and 3%) were added to loess sample, and the particle size distribution, Atterberg limits, collapsibility, and soil water characteristics were analyzed. The results revealed the following. The addition of nanosilica changed the particle size distribution, liquid limit, plastic limit, and plasticity index of loess. After the addition of nanosilica with different contents, the loess collapsibility coefficient curve shifted downward, the soil water retention curve shifted upward, and the unsaturated permeability coefficient curve shifted downward. The pores between particles were filled, and the number of large and medium pores and the pore connectivity were lower after the nanosilica addition. The surface of the coarse particles adsorbed more fine particles, and a large number of micro-aggregates or clay aggregates were present in the pores between particles. In conclusion, the environmentally friendly material nanosilica can be used to improve the hydrological properties of loess, which is applicable to alleviating soil erosion and preventing geological disasters on the Loess Plateau.
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PURPOSE: Invasive fungal diseases, such as pulmonary aspergillosis, are common life-threatening infections in immunocompromised patients and effective treatment is often hampered by delays in timely and specific diagnosis. Fungal-specific molecular imaging ligands can provide non-invasive readouts of deep-seated fungal pathologies. In this study, the utility of antibodies and antibody fragments (Fab) targeting ß-glucans in the fungal cell wall to detect Aspergillus infections was evaluated both in vitro and in preclinical mouse models. METHODS: The binding characteristics of two commercially available ß-glucan antibody clones and their respective antigen-binding Fabs were tested using biolayer interferometry (BLI) assays and immunofluorescence staining. In vivo binding of the Zirconium-89 labeled antibodies/Fabs to fungal pathogens was then evaluated using PET/CT imaging in mouse models of fungal infection, bacterial infection and sterile inflammation. RESULTS: One of the evaluated antibodies (HA-ßG-Ab) and its Fab (HA-ßG-Fab) bound to ß-glucans with high affinity (KD = 0.056 & 21.5 nM respectively). Binding to the fungal cell wall was validated by immunofluorescence staining and in vitro binding assays. ImmunoPET imaging with intact antibodies however showed slow clearance and high background signal as well as nonspecific accumulation in sites of infection/inflammation. Conversely, specific binding of [89Zr]Zr-DFO-HA-ßG-Fab to sites of fungal infection was observed when compared to the isotype control Fab and was significantly higher in fungal infection than in bacterial infection or sterile inflammation. CONCLUSIONS: [89Zr]Zr-DFO-HA-ßG-Fab can be used to detect fungal infections in vivo. Targeting distinct components of the fungal cell wall is a viable approach to developing fungal-specific PET tracers.
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Desferrioxamine B (DFO) is the clinical standard chelator for preparing zirconium-89 labeled antibodies. In the current study, the stabilities of a zirconium-89 labeled panitumumab (PAN; Vectibix®) with three different chelators (DFO, DFO*, and DOTA) were compared. PAN is an anti-HER1/EGFR monoclonal antibody approved by the FDA for the treatment of HER1-expressing colorectal cancers and was used as the model antibody for this study. DFO/DFO* conjugates of PAN were directly radiolabeled with zirconium-89 at room temperature to produce [89Zr]Zr-DFO/DFO*-PAN conjugates following a well-established procedure. A zirconium-89 labeled DOTA-PAN conjugate was prepared by an indirect radiolabeling method. A cyclooctyne-linked DOTA chelator (BCN-DOTA-GA) was first radiolabeled with zirconium-89 at 90 °C under a two-step basic pH adjustment method followed by conjugation with PAN-tetrazene at 37 °C to produce a labeled conjugate, BCN-[89Zr]Zr-DOTA-GA-PAN. High reproducibility of the radiolabeling was observed via this two-step basic pH adjustment. The overall radiochemical yield was 40-50% (n = 12, decay uncorrected) with a radiochemical purity of >95% in 2 h synthesis time. All three conjugates were stable in whole human serum for up to 7 days at 37 °C. The kinetic inertness of the conjugates was assessed against the EDTA challenge. BCN-[89Zr]Zr-DOTA-GA-PAN exhibited excellent inertness followed by [89Zr]Zr-DFO*-PAN. [89Zr]Zr-DFO-PAN displayed the lowest level of inertness.
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Hashimoto's thyroiditis (HT) is the most common organ-specific autoimmune disease, predominantly affecting women. Although the pathogenesis of HT is incompletely understood, some studies have found that macrophage polarization plays a role. Puerarin is a soy isoflavone compound that has anti-inflammatory and immunomodulatory effects and regulates macrophage immune activity. This study aimed to verify the therapeutic effect of puerarin on HT and explored its regulatory effect on macrophage polarization imbalance in HT. Through bioinformatics analysis and molecular biology methods, it was found that macrophages increased significantly in HT patients and model mice. Immunological staining showed that puerarin intervention could reduce tissue inflammatory cell infiltration. Molecular biological examination displayed that puerarin could inhibit local and systemic inflammation levels, and the expression of marker thyroglobulin and thyroid peroxidase Abs. In vivo experimental results indicated that puerarin regulated macrophage polarity and reduced inflammatory damage, possibly by inhibiting the pyroptosis signaling pathway. In vivo macrophage clearance experiments demonstrated that puerarin relied on macrophages to exert its mechanism of action in treating HT. The results of this study indicate that macrophages are important mediators in the development of HT, and puerarin can regulate macrophage polarity and inflammatory status to provide thyroid tissue protection, which provides a new idea for the treatment of HT.
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Isoflavonas , Macrófagos , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Animais , Camundongos , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Humanos , Feminino , Modelos Animais de Doenças , Tireoidite Autoimune/tratamento farmacológico , Tireoidite Autoimune/imunologia , Doença de Hashimoto/tratamento farmacológico , Doença de Hashimoto/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
We combined untargeted and targeted metabolomics to explore the mechanism of blood circulation and blood stasis activation in the traditional Chinese herb pair Panax notoginseng-Salvia miltiorrhiza (PS). In this study, the right hind limb of SD rats was struck by a 1 kg weight, causing traumatic blood stasis (TBS) model, then the rats were gavaged with PS (at ratios of 1:0, 0:1, 3:1, 1:1, and 1:3) for 5 consecutive days. At the end of treatment, blood samples were collected for blood rheology and metabolomics analysis, and muscle tissues of injured limbs were used for HE staining and q-PCR analysis. The results showed that different ratios of PS reduced swelling and improved stasis and blood viscosity in the injured limbs of rats, and intervened in metabolism by modulating 11, 11, 17, 15, and 13 differential metabolites, respectively. The PS (3:1) shows the best treatment effect and the most differential metabolites regression. Targeted metabolomics shows that PS (3:1) can increase the content of AA, and reduce the content of PGF2-α by down-regulating the expression of enzymes Ptgs1 and Cbrl12 and up-regulating the expression of enzyme Hpgd. These results suggested that the PS herb pair exerts its blood stasis activating effects by blocking the conversion of arachidonic acid to prostaglandins.
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Medicamentos de Ervas Chinesas , Panax notoginseng , Salvia miltiorrhiza , Ratos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ácido Araquidônico , Ratos Sprague-Dawley , ProstaglandinasRESUMO
The Miao group is one of the representative Hmong-Mien-speaking populations and primarily scattered in southern China and Southeast Asia, which has experienced massive migrations in history and thus forms distinctive evolutionary genetics. Yet, the genetic explorations of Miao group are relatively limited based on complete mitochondrial genome (mitogenome), especially for the Miao group from Yunnan Province (YNM). Here, we sequenced complete mitogenomes of 132 Miao individuals from Yunnan Province using massively parallel sequencing method. Total 132 Miao individuals could be allocated to 119 various haplotypes, which were mainly dominated by haplogroups prevalent in southern East Asia (B, F, M7 and R9), and rarely occupied by northern lineages (A, D, G and M8). In order to dissect the genetic background of YNM more comprehensively, we introduced 99 published population data with 7135 complete mitochondrial sequences for population genetic comparisons. YNM exhibited closer genetic relationships with Hmong-Mien, Tai-Kadai, Sino-Tibetan and Austroasiatic populations, especially for Hmong-Mien populations; we further speculated that Miao group might have certain direct or indirect gene exchanges with ancient Baiyue groups. Several maternal lineages, such as B5a1c1a, F1g1, B4a5 and D4e1a3, were found to be specifically shared by YNM and other Hmong-Mien populations, and these matrilineal expansions occurred roughly during the Neolithic period. Eventually, according to the population dynamic analyses of YNM, the population size began to emerge recovery â¼1-0.5 kya after a long-term population reduction â¼1-5 kya, during which the B5a1c1a haplogroup manifested relatively apparent lineage expansion.
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População do Leste Asiático , Genoma Mitocondrial , Filogenia , Humanos , China , DNA Mitocondrial/genética , Genética Populacional , Genoma Mitocondrial/genética , Haplótipos , População do Leste Asiático/genéticaRESUMO
Deletion/insertion polymorphism (DIP) is one of the more promising genetic markers in the field of forensic genetics for personal identification and biogeographic ancestry inference. In this research, we used an in-house developed ancestry-informative marker-DIP system, including 56 autosomal diallelic DIPs, three Y-chromosomal DIPs, and an Amelogenin gene, to analyze the genetic polymorphism and ancestral composition of the Chinese Korean group, as well as to explore its genetic relationships with the 26 reference populations. The results showed that this novel panel exhibited high genetic polymorphism in the studied Korean group and could be effectively applied for forensic individual identification in the Korean group. In addition, the results of multiple population genetic analyses indicated that the ancestral component of the Korean group was dominated by northern East Asia. Moreover, the Korean group was more closely related to the East Asian populations, especially to the Japanese population in Tokyo. This study enriched the genetic data of the Korean ethnic group in China and provided information on the ancestry of the Korean group from the perspective of population genetics.
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Etnicidade , Polimorfismo Genético , Humanos , Etnicidade/genética , Genética Populacional , China , República da Coreia , Frequência do Gene , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Sepsis, a critical health condition induced by an overactive innate immune response and reactive oxygen species (ROS)-driven host damage through apoptosis and ferroptosis, continues to pose a significant mortality risk. Despite accumulating evidence of the potential therapeutic properties of tea ingredients, their specific anti-sepsis potential remains inadequately explored. This study comprehensively investigates the targeted genes of tea ingredients, notably epigallocatechin 3-gallate (EGCG), and their correlation with sepsis signature genes. Our findings elucidate that tea ingredients, especially EGCG, exhibit substantial potential in mitigating inflammation and sepsis-induced damage. Through the inhibition of the MAPK cascade and macrophage activation and by impeding the transcriptional activity of RELA (transcription factor p65) in sepsis, EGCG demonstrates significant anti-sepsis efficacy. Molecular docking analysis further underpins this by revealing the close proximity of EGCG and (-)-catechin gallate binding sites to that of RELA on DNA. Subsequent in vitro assays illuminated EGCG's instrumental role in modulating macrophage M2 polarization, balancing M1 and M2 differentiation of bone marrow-derived macrophages (BMDMs), curtailing inflammatory factor secretion, and inhibiting ROS production. Moreover, EGCG effectively suppresses the expression of ferroptosis/apoptosis markers in LPS-induced macrophages during their early stages. Our study advances our understanding of sepsis prevention and treatment strategies, suggesting that tea ingredients such as EGCG could play a pivotal role in developing future sepsis therapies due to their protective effects.
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The application of microfluidic technology in forensic medicine has steadily expanded over the last two decades due to the favorable features of low cost, rapidity, high throughput, user-friendliness, contamination-free, and minimum sample and reagent consumption. In this context, bibliometric methods were adopted to visualize the literature information contained in the Science Citation Index Expanded from 1989 to 2022, focusing on the co-occurrence analysis of forensic and microfluidic topics. A deep interpretation of the literature was conducted based on co-occurrence results, in which microfluidic technologies and their applications in forensic medicine, particularly forensic genetics, were elaborated. The purpose of this review is to provide an impartial evaluation of the utilization of microfluidic technology in forensic medicine. Additionally, the challenges and future trends of implementing microfluidic technology in forensic genetics are also addressed.
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Medicina Legal , Microfluídica , Medicina Legal/métodosRESUMO
OBJECTIVE: This study aimed to investigate the clinical value of the combination detection of captopril renal scintigraphy (CRS) and plasma renin activity (PRA) in the diagnosis of renal hypertension (RHR). METHODS: Retrospective analysis was conducted on the clinical data of 163 patients with suspected RHR admitted to our hospital from March 2019 to March 2021, and all patients underwent blood pressure, CRS and digital subtraction angiography (DSA). The patients were divided into the positive group (n = 100) and the negative group (n = 63) in accordance with the results of DSA examination. PRA, angiotensin II and aldosterone levels of the two groups were detected and compared. The receiver operating characteristic curve was used to analyse the CRS, PRA and combined diagnostic performance. RESULTS: The uptake ratio value after captopril intervention in the positive group was 36.71% ± 8.79%, which was significantly lower than that in the negative group (56.79% ± 10.09%, p < 0.05). The serum PRA level of the positive group was 4.70 ± 1.67 ng/mLêh, which was distinctly higher than that of the negative group (2.12 ± 1.03 ng/mLêh, p < 0.05). The sensitivity and Youden index under the combination detection (area under the curve (AUC) = 0.956, p < 0.001) were all higher than those under single detection. CONCLUSION: The combined detection of PRA and CRS can provide considerable evidence for the early diagnosis and treatment of RHR, which has a certain clinical value.
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Captopril , Hipertensão Renal , Renina , Humanos , Pressão Sanguínea , Captopril/uso terapêutico , Hipertensão Renal/diagnóstico , Cintilografia , Renina/sangue , Estudos RetrospectivosRESUMO
The use of radiolabeled glucose for PET imaging resulted in the most commonly used tracer in the clinic, 2-deoxy-2-[18F]fluoroglucose (FDG). More recently, other radiolabeled sugars have been reported for various applications, including imaging tumors and infections. Therefore, in this study, we developed a series of fluorine-18-labeled L-rhamnose derivatives as potential PET tracers of various fungal and bacterial strains. Acetyl-protected triflate precursors of rhamnose were prepared and radiolabeled with fluorine-18 followed by hydrolysis to produce L-deoxy [18F]fluororhamnose. The overall radiochemical yield was 7-27% in a 90 min synthesis time with a radiochemical purity of 95%. In vivo biodistribution of the ligands using PET imaging showed that 2-deoxy-2-[18F]fluoro-L-rhamnose is stable for at least up to 60 min in mice and eliminated via renal clearance. The tracer also exhibited minimal tissue or skeletal uptake in healthy mice resulting in a low background signal.
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Radioisótopos de Flúor , Ramnose , Camundongos , Animais , Distribuição Tecidual , Linhagem Celular Tumoral , Tomografia por Emissão de Pósitrons/métodos , Compostos RadiofarmacêuticosRESUMO
Over 3 billion doses of inactivated vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been administered globally. However, our understanding of the immune cell functional transcription and T cell receptor (TCR)/B cell receptor (BCR) repertoire dynamics following inactivated SARS-CoV-2 vaccination remains poorly understood. Here, we performed single-cell RNA and TCR/BCR sequencing on peripheral blood mononuclear cells at four time points after immunization with the inactivated SARS-CoV-2 vaccine BBIBP-CorV. Our analysis revealed an enrichment of monocytes, central memory CD4+ T cells, type 2 helper T cells and memory B cells following vaccination. Single-cell TCR-seq and RNA-seq comminating analysis identified a clonal expansion of CD4+ T cells (but not CD8+ T cells) following a booster vaccination that corresponded to a decrease in the TCR diversity of central memory CD4+ T cells and type 2 helper T cells. Importantly, these TCR repertoire changes and CD4+ T cell differentiation were correlated with the biased VJ gene usage of BCR and the antibody-producing function of B cells post-vaccination. Finally, we compared the functional transcription and repertoire dynamics in immune cells elicited by vaccination and SARS-CoV-2 infection to explore the immune responses under different stimuli. Our data provide novel molecular and cellular evidence for the CD4+ T cell-dependent antibody response induced by inactivated vaccine BBIBP-CorV. This information is urgently needed to develop new prevention and control strategies for SARS-CoV-2 infection. (ClinicalTrials.gov Identifier: NCT04871932).
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Vacinas contra COVID-19 , COVID-19 , Humanos , COVID-19/prevenção & controle , Leucócitos Mononucleares , SARS-CoV-2 , Receptores de Antígenos de Linfócitos B , Imunização Secundária , Análise de Sequência de RNA , Anticorpos AntiviraisRESUMO
Introduction: Left-sided appendicitis is a rare condition, and we report a patient with left abdominal heterotopia of the right colon complicated by acute appendicitis in the left lower quadrant. Case presentation: A 39-year-old male was admitted to hospital following left lower abdominal pain for 1 day. Imaging examination by abdominal CT showed that the appendix was not clearly seen, and a mass was found in the left lower abdomen. Because the patient's abdominal pain was severe and the current diagnosis was not clear, after soliciting the patient's consent, we performed laparoscopic exploration. This exploration revealed that the cecum and ascending colon were located in the left iliac fossa, the appendix was swollen, the length of the appendix was approximately 6â cm, the diameter of the appendix was approximately 1â cm, and there was pus moss attached to the surface. We performed a laparoscopic appendectomy; the procedure was uneventful and the patient was discharged 3 days after the procedure. Conclusion: Left-sided appendicitis is a rare condition and is therefore easy to misdiagnose. Wrong diagnosis can lead to serious complications and endanger the patient's life. Therefore, a full combination of laboratory tests and CT scan is required. If still no diagnosis can be made correctly, a laparoscopic exploration needs to be performed in a timely manner. This case teaches us that when we encounter a patient with severe left abdominal pain that cannot be definitely diagnosed, we need to be vigilant and perform timely laparoscopic exploration when necessary.
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BACKGROUND: Several new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model. METHODS: Twenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of [18F]FLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination. RESULTS: [18F]FLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm [18F]FLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy. CONCLUSION: Significant decreases in [18F]FLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of [18F]FLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.
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Didesoxinucleosídeos , Neoplasias da Bexiga Urinária , Animais , Biomarcadores , Linhagem Celular Tumoral , Didesoxinucleosídeos/metabolismo , Humanos , Camundongos , Piperazinas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Piridinas , Temozolomida/uso terapêutico , Timidina , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused millions of deaths and lacks treatment. Although several studies have focused on the major component of green tea, epigallocatechin 3-gallate (EGCG), which is efficient in preventing COVID-19, systemic analyses of the anti-COVID-19 potential of green tea remain insufficient. Here, we co-analyzed the target genes of tea ingredients and COVID-19 signature genes and found that epigallocatechin 3-acetalbehyde was capable of reversing the major molecular processes of COVID-19 (MAPK and NF-κB activation). These findings were further supported by Western blotting (WB), immunofluorescence, and quantitative polymerase chain reaction (qPCR) in LPS-stimulated macrophages. Moreover, using molecular docking analysis, we identified three tea ingredients ((-)-catechin gallate, D-(+)-cellobiose, and EGCG) that may interact with the vital SARS-CoV-2 protein, 5R84, compared with the qualified 5R84 ligand WGS. Thus, our results indicated that tea ingredients have the potential to treat COVID-19 by suppressing the COVID-19 signature genes and interacting with the vital SARS-CoV-2 protein.
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Network traffic prediction is an important tool for the management and control of IoT, and timely and accurate traffic prediction models play a crucial role in improving the IoT service quality. The degree of burstiness in intelligent network traffic is high, which creates problems for prediction. To address the problem faced by traditional statistical models, which cannot effectively extract traffic features when dealing with inadequate sample data, in addition to the poor interpretability of deep models, this paper proposes a prediction model (fusion prior knowledge network) that incorporates prior knowledge into the neural network training process. The model takes the self-similarity of network traffic as a priori knowledge, incorporates it into the gating mechanism of the long short-term memory neural network, and combines a one-dimensional convolutional neural network with an attention mechanism to extract the temporal features of the traffic sequence. The experiments show that the model can better recover the characteristics of the original data. Compared with the traditional prediction model, the proposed model can better describe the trend of network traffic. In addition, the model produces an interpretable prediction result with an absolute correction factor of 76.4%, which is at least 10% better than the traditional statistical model.
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Memória de Longo Prazo , Redes Neurais de Computação , InteligênciaRESUMO
AIMS: Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported. METHODS AND RESULTS: Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbß3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway. CONCLUSION: We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.
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Relógios Circadianos , Trombose , Animais , Plaquetas/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Humanos , Camundongos , Camundongos Knockout , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Ativação PlaquetáriaRESUMO
Wireless distributed storage is beneficial in the provision of reliable content storage and offloading of cellular traffic. In this paper, we consider a cellular device-to-device (D2D) underlay-based wireless distributed storage system, in which the minimum storage regenerating (MSR) coding combined with the partial downloading scheme is employed. To alleviate burdens on insufficient cellular resources and improve spectral efficiency in densely deployed networks, multiple storage devices can simultaneously use the same uplink cellular subchannel under the non-orthogonal multiple access (NOMA) protocol. Our objective is to minimize the total transmission power for content reconstruction, while guaranteeing the signal-to-interference-plus-noise ratio (SINR) constraints for cellular users by jointly optimizing power and subchannel allocation. To tackle the non-convex combinational program, we decouple the original problem into two subproblems and propose two low-complexity algorithms to efficiently solve them, followed by a joint optimization, implemented by alternately updating the solutions to each subproblem. The numerical results illustrate that our proposed algorithms are capable of performing an exhaustive search with lower computation complexity, and the NOMA-enhanced scheme provides more transmission opportunities for neighbor storage devices, thus significantly reducing the total power consumption.
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Algoritmos , Redes de Comunicação de Computadores , Razão Sinal-RuídoRESUMO
OBJECTIVE: To introduce the test methods of embryo toxicity applied to medical devices for human assisted reproductive technology (ARTMD), and provide the evaluation reference. METHODS: The embryo toxicity test methods of ARTMD were summarized, and the key procedures and challenges in their safety evaluation were also discussed. RESULTS: Establishing sensitive and stable test system is important to guarantee the safety and efficacy of ARTMD. CONCLUSIONS: It remains development opportunities in improving sample preparation, extending test technology and expending evaluation method.