ABSTRACT
BACKGROUND AND AIMS: Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. METHODS: NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. RESULTS: Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. CONCLUSIONS: This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.
ABSTRACT
Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe2+) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.
ABSTRACT
The proliferation and differentiation of skeletal muscle satellite cells is a complex physiological process involving various transcription factors and small RNA molecules. This study aimed to understand the regulatory mechanisms underlying these processes, focusing on interferon-related development factor 2 (IFRD2) as a target gene of miRNA-2400 in bovine skeletal MuSCs (MuSCs). IFRD2 was identified as a target gene of miRNA-2400 involved in regulating the proliferation and differentiation of bovine skeletal MuSCs. Our results indicate that miR-2400 can target binding the 3'UTR of IFRD2 and inhibit its translation. mRNA and protein expression levels of IFRD2 increased significantly with increasing days of differentiation. Moreover, overexpression of the IFRD2 gene inhibited proliferation and promoted differentiation of bovine MuSCs. Conversely, the knockdown of the gene had the opposite effect. Overexpression of IFRD2 resulted in the inhibition of ERK1/2 phosphorylation levels in bovine MuSCs, which in turn promoted differentiation. In summary, IFRD2, as a target gene of miR-2400, crucially affects bovine skeletal muscle proliferation and differentiation by precisely regulating ERK1/2 phosphorylation.
ABSTRACT
Bleomycins (BLMs) are widely used in clinics as antitumor agents. However, BLM-based chemotherapies often accompany severe pulmonary fibrosis (PF). Human bleomycin hydrolase is a cysteine protease that can convert BLMs into inactive deamido-BLMs. In this study, mannose-modified hierarchically porous UiO-66 (MHP-UiO-66) nanoparticles (NPs) were used to encapsulate the recombinant human bleomycin hydrolase (rhBLMH). When rhBLMH@MHP-UiO-66 was intratracheally instilled into the lungs, the NPs were transported into the epithelial cells, and rhBLMH prevented the lungs from PF during BLM-based chemotherapies. Encapsulation of rhBLMH in the MHP-UiO-66 NPs protects the enzyme from proteolysis in physiological conditions and enhances cellular uptake. In addition, the MHP-UiO-66 NPs significantly enhance the pulmonary accumulation of intratracheally instilled rhBLMH, thus providing more efficient protection of the lungs against BLMs during the chemotherapies.
Subject(s)
Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/prevention & control , Bleomycin/pharmacology , Mannose , Porosity , Lung/pathologyABSTRACT
BACKGROUND: Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI. METHODS: Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified Lrg1, Vegf-a, and IL-10 as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR. RESULTS: We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1ß-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI. CONCLUSIONS: Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.
Subject(s)
Histones , Myocardial Infarction , Humans , Histones/metabolism , Transcriptional Activation , Myocardial Infarction/metabolism , Macrophages/metabolism , Monocytes/metabolismABSTRACT
Human bleomycin hydrolase (hBH) catalyzes deamidation of the anticancer drug bleomycins (BLM). This enzyme is involved in BLM detoxification and drug resistance. Herein, we report the putative BLM-binding site and catalytic mechanism of hBH. The crystal structures and biochemical studies suggest that hBH cleaves its C-terminal residue without significant preference for the type of amino acid, and therefore can accordingly accommodate the ß-aminoalanine amide moiety of BLM for deamidation. Interestingly, hBH is capable of switching from a cysteine protease to a serine protease that is unable to cleave the secondary amide of hBH C-terminus but reacts with the primary amide of BLMs.
Subject(s)
Cysteine Proteases , Amides , Bleomycin/metabolism , Bleomycin/pharmacology , Cysteine Endopeptidases , Cysteine Proteases/metabolism , Humans , Mutation , Serine Proteases/metabolism , Structure-Activity RelationshipABSTRACT
Sucrose is the central unit of carbon and energy in plants. Active intercellular transport of sucrose is mediated by sucrose transporters (SUTs), genes for which have been found in the genomes of all land plants. However, they have only been assigned functions in angiosperm species. Here, we cloned two types of SUTs from two gymnosperms, the conifers Cedrus deodara (Roxb. G. Don) and Pinus massoniana Lambert, and analyzed their sucrose transport activities. Uptake of the fluorescent sucrose-analog esculin into tobacco epidermis cells expressing the conifer SUT confirmed their transport ability. To determine their function in planta, we investigated their mRNA abundance in relation to photosynthesis and sugar levels in leaves, inner bark, wood and roots. Combined with measurements of protein abundance and immunolocalization of C. deodara SUTs, our results suggest a role for CdSUT1G and CdSUT2 in supporting phloem transport under varying environmental conditions. The implications of these findings regarding conifer physiology and SUT evolution are discussed.
Subject(s)
Sucrose , Tracheophyta , Biological Transport , Membrane Transport Proteins/genetics , Phloem/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Sucrose/metabolism , Sugars/metabolism , Tracheophyta/metabolismABSTRACT
Objective: To investigate the effect of SIX2 gene on the proliferation of bovine skeletal muscle satellite cells. Methods: Bovine skeletal muscle satellite cells were used as experimental materials, and the expression of SIX2 gene in bovine skeletal muscle satellite cells was detected by real-time quantitative PCR at 24 h, 48 h, and 72 h of proliferation. The SIX2 gene overexpression vector was constructed by homologous recombination. The SIX2 gene overexpression plasmid and the control empty plasmid were transfected into bovine skeletal muscle satellite cells, and each group had three complex Wells. The cell viability was detected by MTT assay at 24 h, 48 h and 72 h after transfection. At 48 h after transfection, the cell cycle was detected by flow cytometry, and the expressions of cell proliferation marker genes were detected by real-time quantitative PCR (qRT-PCR) and Western blot. Results: With the proliferation of bovine skeletal muscle satellite cells, the expression of SIX2 mRNA was increased. Compared with the control group, the expressions of SIX2 mRNA and protein in the SIX2 gene overexpression plasmid group were increased by 18 and 2.6 times, respectively (Pï¼0.01). The cell viability of the SIX2 gene overexpression plasmid group was increased (Pï¼0.01), the proportion of G1 cells was decreased by 24.6%, and the proportion of S phase and G2 phase cells was increased by 20.3% and 4.31%, respectively (Pï¼0.01). The mRNA and protein expressions of Pax7 gene were increased by 15.84 and 1.22 times, respectively, and the mRNA and protein expressions of proliferation marker genes PCNA and CCNB1 were increased by 4.82, 2.23,1.55 and 1.46 times, respectively (Pï¼0.01). Conclusion: Overexpression of SIX2 gene promotes the proliferation of bovine skeletal muscle satellite cells.
Subject(s)
Satellite Cells, Skeletal Muscle , Cattle , Animals , Cell Cycle , Cell Proliferation , RNA, Messenger , Transcription FactorsABSTRACT
In this work, we describe genetic tools and techniques for engineering Thermoanaerobacterium saccharolyticum. In particular, the T. saccharolyticum transformation protocol and the methods for selecting for transformants are described. Methods for determining strain phenotypes are also presented.
Subject(s)
Metabolic Engineering/methods , Thermoanaerobacterium/metabolism , Bacterial Proteins/metabolism , Enzyme Assays , Fermentation , Gene Deletion , Gene Expression Regulation, Bacterial , Genetic Engineering , Phenotype , Promoter Regions, Genetic/genetics , RNA, Ribosomal, 16S/genetics , Thermoanaerobacterium/genetics , Transformation, GeneticABSTRACT
Thermoanaerobacterium saccharolyticum is an anaerobic thermophile that can ferment hemicellulose to produce biofuels, such as ethanol. It has been engineered to produce ethanol at high yield and titer. T. saccharolyticum uses the Embden-Meyerhof-Parnas (EMP) pathway for glycolysis. However, the genes and enzymes used in each step of the EMP pathway in T. saccharolyticum are not completely known. In T. saccharolyticum, both pyruvate kinase (PYK) and pyruvate phosphate dikinase (PPDK) are highly expressed based on transcriptomic and proteomic data. Both enzymes catalyze the formation of pyruvate from phosphoenolpyruvate (PEP). PYK is typically the last step of EMP glycolysis pathway while PPDK is reversible and is found mostly in C4 plants and some microorganisms. It is not clear what role PYK and PPDK play in T. saccharolyticum metabolism and fermentation pathways and whether both are necessary. In this study we deleted the ppdk gene in wild type and homoethanologen strains of T. saccharolyticum and showed that it is not essential for growth or ethanol production.
ABSTRACT
The genomes of most cellulolytic clostridia do not contain genes annotated as transaldolase. Therefore, for assimilating pentose sugars or for generating C5 precursors (such as ribose) during growth on other (non-C5) substrates, they must possess a pathway that connects pentose metabolism with the rest of metabolism. Here we provide evidence that for this connection cellulolytic clostridia rely on the sedoheptulose 1,7-bisphosphate (SBP) pathway, using pyrophosphate-dependent phosphofructokinase (PPi-PFK) instead of transaldolase. In this reversible pathway, PFK converts sedoheptulose 7-phosphate (S7P) to SBP, after which fructose-bisphosphate aldolase cleaves SBP into dihydroxyacetone phosphate and erythrose 4-phosphate. We show that PPi-PFKs of Clostridium thermosuccinogenes and Clostridium thermocellum indeed can convert S7P to SBP, and have similar affinities for S7P and the canonical substrate fructose 6-phosphate (F6P). By contrast, (ATP-dependent) PfkA of Escherichia coli, which does rely on transaldolase, had a very poor affinity for S7P. This indicates that the PPi-PFK of cellulolytic clostridia has evolved the use of S7P. We further show that C. thermosuccinogenes contains a significant SBP pool, an unusual metabolite that is elevated during growth on xylose, demonstrating its relevance for pentose assimilation. Last, we demonstrate that a second PFK of C. thermosuccinogenes that operates with ATP and GTP exhibits unusual kinetics toward F6P, as it appears to have an extremely high degree of cooperative binding, resulting in a virtual on/off switch for substrate concentrations near its K½ value. In summary, our results confirm the existence of an SBP pathway for pentose assimilation in cellulolytic clostridia.
Subject(s)
Clostridiales/genetics , Clostridium thermocellum/genetics , Fructose-Bisphosphate Aldolase/genetics , Pentose Phosphate Pathway/genetics , Phosphofructokinase-1/genetics , Clostridiales/enzymology , Clostridium thermocellum/enzymology , Dihydroxyacetone Phosphate/genetics , Dihydroxyacetone Phosphate/metabolism , Escherichia coli/enzymology , Fructose-Bisphosphate Aldolase/metabolism , Fructosephosphates/metabolism , Kinetics , Pentoses/biosynthesis , Pentoses/metabolism , Phosphofructokinase-1/metabolism , Phosphotransferases/metabolism , Ribose/biosynthesis , Ribose/metabolism , Sugar Phosphates/metabolism , Transaldolase/genetics , Transaldolase/metabolism , Xylose/biosynthesis , Xylose/metabolismABSTRACT
BACKGROUND: Biofuel production from plant cell walls offers the potential for sustainable and economically attractive alternatives to petroleum-based products. In particular, Clostridium thermocellum is a promising host for consolidated bioprocessing (CBP) because of its strong native ability to ferment cellulose. RESULTS: We tested 12 different enzyme combinations to identify an n-butanol pathway with high titer and thermostability in C. thermocellum. The best producing strain contained the thiolase-hydroxybutyryl-CoA dehydrogenase-crotonase (Thl-Hbd-Crt) module from Thermoanaerobacter thermosaccharolyticum, the trans-enoyl-CoA reductase (Ter) enzyme from Spirochaeta thermophila and the butyraldehyde dehydrogenase and alcohol dehydrogenase (Bad-Bdh) module from Thermoanaerobacter sp. X514 and was able to produce 88 mg/L n-butanol. The key enzymes from this combination were further optimized by protein engineering. The Thl enzyme was engineered by introducing homologous mutations previously identified in Clostridium acetobutylicum. The Hbd and Ter enzymes were engineered for changes in cofactor specificity using the CSR-SALAD algorithm to guide the selection of mutations. The cofactor engineering of Hbd had the unexpected side effect of also increasing activity by 50-fold. CONCLUSIONS: Here we report engineering C. thermocellum to produce n-butanol. Our initial pathway designs resulted in low levels (88 mg/L) of n-butanol production. By engineering the protein sequence of key enzymes in the pathway, we increased the n-butanol titer by 2.2-fold. We further increased n-butanol production by adding ethanol to the growth media. By combining all these improvements, the engineered strain was able to produce 357 mg/L of n-butanol from cellulose within 120 h.
ABSTRACT
The thermophilic anaerobes Thermoanaerobacterium saccharolyticum and Clostridium thermocellum are good candidates for lignocellulosic ethanol production. T. saccharolyticum has been successfully engineered to produce ethanol at high titer (70â¯g/L). The maximum ethanol titer of engineered strains of C. thermocellum is only 25â¯g/L. We hypothesize that one or more of the enzymes in the ethanol production pathway in C. thermocellum is not adequate for ethanol production at high titer. In this study, we focused on the enzymes responsible for the part of the ethanol production pathway from pyruvate to ethanol. In T. saccharolyticum, we replaced all of the genes encoding proteins in this pathway with their homologs from C. thermocellum and examined what combination of gene replacements restricted ethanol titer. We found that a pathway consisting of Ct_nfnAB, Ct_fd, Ct_adhE and Ts_pforA was sufficient to support ethanol titer greater than 50â¯g/L, however replacement of Ts_pforA by Ct_pfor1 dramatically decreased the maximum ethanol titer to 14â¯g/L. We then demonstrated that the reason for reduced ethanol production is that the Ct_pfor1 is inhibited by accumulation of ethanol and NADH, while Ts_pforA is not.
Subject(s)
Alcohol Dehydrogenase/metabolism , Aldehyde Dehydrogenase/metabolism , Clostridium thermocellum/metabolism , Ferredoxins/metabolism , NADH, NADPH Oxidoreductases/metabolism , Pyruvate Synthase/metabolism , Thermoanaerobacterium/metabolism , Alcohol Dehydrogenase/genetics , Aldehyde Dehydrogenase/genetics , Clostridium thermocellum/genetics , Fermentation , Ferredoxins/genetics , Metabolic Engineering , NADH, NADPH Oxidoreductases/genetics , Plasmids/geneticsABSTRACT
BACKGROUND: Clostridium thermocellum has been the subject of multiple metabolic engineering strategies to improve its ability to ferment cellulose to ethanol, with varying degrees of success. For ethanol production in C. thermocellum, the conversion of pyruvate to acetyl-CoA is catalyzed primarily by the pyruvate ferredoxin oxidoreductase (PFOR) pathway. Thermoanaerobacterium saccharolyticum, which was previously engineered to produce ethanol of high yield (> 80%) and titer (70 g/L), also uses a pyruvate ferredoxin oxidoreductase, pforA, for ethanol production. RESULTS: Here, we introduced the T. saccharolyticum pforA and ferredoxin into C. thermocellum. The introduction of pforA resulted in significant improvements to ethanol yield and titer in C. thermocellum grown on 50 g/L of cellobiose, but only when four other T. saccharolyticum genes (adhA, nfnA, nfnB, and adhEG544D ) were also present. T. saccharolyticum ferredoxin did not have any observable impact on ethanol production. The improvement to ethanol production was sustained even when all annotated native C. thermocellum pfor genes were deleted. On high cellulose concentrations, the maximum ethanol titer achieved by this engineered C. thermocellum strain from 100 g/L Avicel was 25 g/L, compared to 22 g/L for the reference strain, LL1319 (adhA(Tsc)-nfnAB(Tsc)-adhEG544D (Tsc)) under similar conditions. In addition, we also observed that deletion of the C. thermocellum pfor4 results in a significant decrease in isobutanol production. CONCLUSIONS: Here, we demonstrate that the pforA gene can improve ethanol production in C. thermocellum as part of the T. saccharolyticum pyruvate-to-ethanol pathway. In our previous strain, high-yield (~ 75% of theoretical) ethanol production could be achieved with at most 20 g/L substrate. In this strain, high-yield ethanol production can be achieved up to 50 g/L substrate. Furthermore, the introduction of pforA increased the maximum titer by 14%.
ABSTRACT
BACKGROUND: Clostridium thermocellum is a cellulolytic anaerobic thermophile that is a promising candidate for consolidated bioprocessing of lignocellulosic biomass into biofuels such as ethanol. It was previously shown that expressing Thermoanaerobacterium saccharolyticum adhA in C. thermocellum increases ethanol yield.In this study, we investigated expression of adhA genes from different organisms in Clostridium thermocellum. METHODS: Based on sequence identity to T. saccharolyticum adhA, we chose adhA genes from 10 other organisms: Clostridium botulinum, Methanocaldococcus bathoardescens, Thermoanaerobacterium ethanolicus, Thermoanaerobacter mathranii, Thermococcus strain AN1, Thermoanaerobacterium thermosaccharolyticum, Caldicellulosiruptor saccharolyticus, Fervidobacterium nodosum, Marinitoga piezophila, and Thermotoga petrophila. All 11 adhA genes (including T. saccharolyticum adhA) were expressed in C. thermocellum and fermentation end products were analyzed. RESULTS: All 11 adhA genes increased C. thermocellum ethanol yield compared to the empty-vector control. C. botulinum and T. ethanolicus adhA genes generated significantly higher ethanol yield than T. saccharolyticum adhA. CONCLUSION: Our results indicated that expressing adhA is an effective method of increasing ethanol yield in wild-type C. thermocellum, and that this appears to be a general property of adhA genes.
ABSTRACT
The metabolism of Clostridium thermocellum is notable in that it assimilates sugar via the EMP pathway but does not possess a pyruvate kinase enzyme. In the wild type organism, there are three proposed pathways for conversion of phosphoenolpyruvate (PEP) to pyruvate, which differ in their cofactor usage. One path uses pyruvate phosphate dikinase (PPDK), another pathway uses the combined activities of PEP carboxykinase (PEPCK) and oxaloacetate decarboxylase (ODC). Yet another pathway, the malate shunt, uses the combined activities of PEPCK, malate dehydrogenase and malic enzyme. First we showed that there is no flux through the ODC pathway by enzyme assay. Flux through the remaining two pathways (PPDK and malate shunt) was determined by dynamic 13C labeling. In the wild-type strain, the malate shunt accounts for about 33±2% of the flux to pyruvate, with the remainder via the PPDK pathway. Deletion of the ppdk gene resulted in a redirection of all pyruvate flux through the malate shunt. This provides the first direct evidence of the in-vivo function of the malate shunt.
Subject(s)
Biosynthetic Pathways/physiology , Clostridium thermocellum/physiology , Malates/metabolism , Metabolic Flux Analysis/methods , Phosphoenolpyruvate/metabolism , Pyruvate Kinase/metabolism , Pyruvic Acid/metabolism , Carbon-13 Magnetic Resonance Spectroscopy/methods , Glucose/metabolism , Glycolysis/physiology , Metabolic Networks and Pathways/physiology , Models, Biological , Pyruvic Acid/isolation & purificationABSTRACT
N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Pancreatic Neoplasms/genetics , Precision Medicine/methods , Xenograft Model Antitumor Assays/methods , Animals , Biopsy, Fine-Needle , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Humans , Male , Mice , Mice, Inbred NOD , Neoplasm Metastasis , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Proof of Concept StudyABSTRACT
In this paper, participants operated visual display terminals (VDT); the authors analyzed their pulse wave signals to develop objective indices for diagnosing and assessing VDT-induced. The experiment used 30 healthy undergraduates test subjects; each subject operated static PC for 4 hours. The pulse waves of local blood volumes in the test subjects' finger-tips were measured every 30 minutes for 2 minutes. After the experiment, the pulse wave parameters were analyzed. All test subjects exhibited signs of visual fatigue according to the fatigue scale results. There were significant differences of heart rate (HR), which clearly declined before and after the experiment (P<0.01). The indexes RMSSD, SDNN, P3, P4, P5, P6, and TP had significant differences (P<0.01) and all rose. The positions of the main and dicrotic waves advanced (P<0.01). The experiment parameters prompted significant changes; pulse wave forms changed during VDT work. Based on these results, pulse wave analysis holds promise as an effective, noninvasive technique for measuring VDT fatigue.
Subject(s)
Blood Volume , Heart Rate , Mental Fatigue/physiopathology , Pulse Wave Analysis/methods , User-Computer Interface , Visual Perception , Computer Terminals , Female , Humans , Male , Mental Fatigue/diagnosis , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
This study aimed to investigate the athletic differences in the characteristics of the photoplethysmographic (PPG) pulse shape. 304 athletes were enrolled and divided into three subgroups according to a typical sport classification in terms of the maximal oxygen uptake (MaxO2_low, MaxO2_middle and MaxO2_high groups) or the maximal muscular voluntary contraction (MMVC_low, MMVC_middle, and MMVC_high groups). Finger PPG pulses were digitally recorded and then normalized to derive the pulse area, pulse peak time T p , dicrotic notch time T n , and pulse reflection index (RI). The four parameters were finally compared between the three subgroups categorized by MaxO2 or by MMVC. In conclusion, it has been demonstrated by quantifying the characteristics of the PPG pulses in different athletes that MaxO2, but not MMVC, had significant effect on the arterial properties.