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Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue the learning/memory deficits observed in Alzheimer's disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.
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Maladie d'Alzheimer , Troubles de la mémoire , Apprentissage spatial , Animaux , Mâle , Souris , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Modèles animaux de maladie humaine , Hippocampe/métabolisme , Hippocampe/effets des médicaments et des substances chimiques , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Apprentissage du labyrinthe/physiologie , Troubles de la mémoire/traitement médicamenteux , Troubles de la mémoire/métabolisme , Souris transgéniques , Microtubules/métabolisme , Microtubules/effets des médicaments et des substances chimiques , Apprentissage spatial/effets des médicaments et des substances chimiques , Protéines tau/métabolisme , Dynamine-I/métabolismeRÉSUMÉ
Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.
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Instabilité des chromosomes , Évolution de la maladie , Tumeurs du pancréas , Animaux , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/génétique , Tumeurs du pancréas/métabolisme , Souris , Humains , Épithélioma in situ/anatomopathologie , Épithélioma in situ/génétique , Épithélioma in situ/métabolisme , Cellules stromales/métabolisme , Cellules stromales/anatomopathologie , Microenvironnement tumoral , Mécanotransduction cellulaire , Focal adhesion kinase 1RÉSUMÉ
MOTIVATION: Single-cell RNA-seq normalization is an essential step to correct unwanted biases caused by sequencing depth, capture efficiency, dropout, and other technical factors. Existing normalization methods primarily reduce biases arising from sequencing depth by modeling count-depth relationship and/or assuming a specific distribution for read counts. However, these methods may lead to over or under-correction due to presence of technical biases beyond sequencing depth and the restrictive assumption on models and distributions. RESULTS: We present scKWARN, a Kernel Weighted Average Robust Normalization designed to correct known or hidden technical confounders without assuming specific data distributions or count-depth relationships. scKWARN generates a pseudo expression profile for each cell by borrowing information from its fuzzy technical neighbors through a kernel smoother. It then compares this profile against the reference derived from cells with the same bimodality patterns to determine the normalization factor. As demonstrated in both simulated and real datasets, scKWARN outperforms existing methods in removing a variety of technical biases while preserving true biological heterogeneity. AVAILABILITY AND IMPLEMENTATION: scKWARN is freely available at https://github.com/cyhsuTN/scKWARN.
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Analyse sur cellule unique , Analyse de l'expression du gène de la cellule unique , Analyse de séquence d'ARN/méthodes , , Analyse de profil d'expression de gènes , LogicielRÉSUMÉ
Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics.
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Glutathion , Mitochondries , Espèces réactives de l'oxygène/métabolisme , Glutathion/métabolisme , Mitochondries/métabolisme , Stress oxydatif/physiologie , Homéostasie , OxydoréductionRÉSUMÉ
OBJECTIVE: We aimed to compare the prevalence and neonatal mortality associated with large for gestational age (LGA) and macrosomia among 115.6 million live births in 15 countries, between 2000 and 2020. DESIGN: Population-based, multi-country study. SETTING: National healthcare systems. POPULATION: Liveborn infants. METHODS: We used individual-level data identified for the Vulnerable Newborn Measurement Collaboration. We calculated the prevalence and relative risk (RR) of neonatal mortality among live births born at term + LGA (>90th centile, and also >95th and >97th centiles when the data were available) versus term + appropriate for gestational age (AGA, 10th-90th centiles) and macrosomic (≥4000, ≥4500 and ≥5000 g, regardless of gestational age) versus 2500-3999 g. INTERGROWTH 21st served as the reference population. MAIN OUTCOME MEASURES: Prevalence and neonatal mortality risks. RESULTS: Large for gestational age was common (median prevalence 18.2%; interquartile range, IQR, 13.5%-22.0%), and overall was associated with a lower neonatal mortality risk compared with AGA (RR 0.83, 95% CI 0.77-0.89). Around one in ten babies were ≥4000 g (median prevalence 9.6% (IQR 6.4%-13.3%), with 1.2% (IQR 0.7%-2.0%) ≥4500 g and with 0.2% (IQR 0.1%-0.2%) ≥5000 g). Overall, macrosomia of ≥4000 g was not associated with increased neonatal mortality risk (RR 0.80, 95% CI 0.69-0.94); however, a higher risk was observed for birthweights of ≥4500 g (RR 1.52, 95% CI 1.10-2.11) and ≥5000 g (RR 4.54, 95% CI 2.58-7.99), compared with birthweights of 2500-3999 g, with the highest risk observed in the first 7 days of life. CONCLUSIONS: In this population, birthweight of ≥4500 g was the most useful marker for early mortality risk in big babies and could be used to guide clinical management decisions.
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Patients who have recovered from coronavirus disease 2019 (COVID-19) infection may experience chronic fatigue when exercising, despite no obvious heart or lung abnormalities. The present lack of effective treatments makes managing long COVID a major challenge. One of the underlying mechanisms of long COVID may be mitochondrial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can alter the mitochondria responsible for energy production in cells. This alteration leads to mitochondrial dysfunction which, in turn, increases oxidative stress. Ultimately, this results in a loss of mitochondrial integrity and cell death. Moreover, viral proteins can bind to mitochondrial complexes, disrupting mitochondrial function and causing the immune cells to over-react. This over-reaction leads to inflammation and potentially long COVID symptoms. It is important to note that the roles of mitochondrial damage and inflammatory responses caused by SARS-CoV-2 in the development of long COVID are still being elucidated. Targeting mitochondrial function may provide promising new clinical approaches for long-COVID patients; however, further studies are needed to evaluate the safety and efficacy of such approaches.
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COVID-19 , Maladies mitochondriales , Humains , SARS-CoV-2 , Syndrome de post-COVID-19 , InflammationRÉSUMÉ
Acute epiglottitis (AE) is a life-threatening condition and needs to be recognized timely. Diagnosis of AE with a lateral neck radiograph yields poor reliability and sensitivity. Convolutional neural networks (CNN) are powerful tools to assist the analysis of medical images. This study aimed to develop an artificial intelligence model using CNN-based transfer learning to identify AE in lateral neck radiographs. All cases in this study are from two hospitals, a medical center, and a local teaching hospital in Taiwan. In this retrospective study, we collected 251 lateral neck radiographs of patients with AE and 936 individuals without AE. Neck radiographs obtained from patients without and with AE were used as the input for model transfer learning in a pre-trained CNN including Inception V3, Densenet201, Resnet101, VGG19, and Inception V2 to select the optimal model. We used five-fold cross-validation to estimate the performance of the selected model. The confusion matrix of the final model was analyzed. We found that Inception V3 yielded the best results as the optimal model among all pre-train models. Based on the average value of the fivefold cross-validation, the confusion metrics were obtained: accuracy = 0.92, precision = 0.94, recall = 0.90, and area under the curve (AUC) = 0.96. Using the Inception V3-based model can provide an excellent performance to identify AE based on radiographic images. We suggest using the CNN-based model which can offer a non-invasive, accurate, and fast diagnostic method for AE in the future.
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Apprentissage profond , Épiglottite , Humains , Intelligence artificielle , Épiglottite/imagerie diagnostique , Études rétrospectives , Reproductibilité des résultats , , Maladie aigüeRÉSUMÉ
The immunoreactivity or/and stress response can be induced by nanomaterials' different properties, such as size, shape, etc. These effects are, however, not yet fully understood. This study aimed to clarify the effects of SiO2 nanofibers (SiO2NFs) on the cellular responses of THP-1-derived macrophage-like cells. The effects of SiO2NFs with different lengths on reactive oxygen species (ROS) and pro-inflammatory cytokines TNF-α and IL-1ß in THP-1 cells were evaluated. From the two tested lengths, it was only the L-SiO2NFs with a length ≈ 44 ± 22 µm that could induce ROS. Compared to this, only S-SiO2NFs with a length ≈ 14 ± 17 µm could enhance TNF-α and IL-1ß expression. Our results suggested that L-SiO2NFs disassembled by THP-1 cells produced ROS and that the inflammatory reaction was induced by the uptake of S-SiO2NFs by THP-1 cells. The F-actin staining results indicated that SiO2NFs induced cell motility and phagocytosis. There was no difference in cytotoxicity between L- and S-SiO2NFs. However, our results suggested that the lengths of SiO2NFs induced different cellular responses.
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Silice , Facteur de nécrose tumorale alpha , Cytokines/métabolisme , Humains , Macrophages , Espèces réactives de l'oxygène/métabolisme , Silice/pharmacologie , Cellules THP-1 , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
Controlling the corrosion rate of implants to maintain mechanical properties during tissue healing is significant in developing magnesium alloy implants. In addition to surface treatment and material properties, the study of geometric alteration and mechanical strength are also vital for implant development. In this study, we developed a three-dimensional model for semi-autonomous computational pitting corrosion. It is based on the Monte Carlo method, modeling magnesium alloy implants toward clinical application. The corrosion probability is based on the number of exposed surfaces to saline and the oxidation characteristics of the elements. The computational results are well compared with the experimental measurement using micro-computed tomography (micro-CT) in 500 h. Subsequently, the computational analysis is extended to 3,000 h of corrosion analysis. The 3D model appears promising to assist the development of biodegradable implants.
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BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. RESEARCH QUESTION: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity? STUDY DESIGN AND METHODS: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. RESULTS: Twenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs -40.2 ± 21.3 mL/min; P < .05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak vs rest Vo2 (25.9 ± 15.3 mL/min vs -60.8 ± 25.6 mL/min; P < .01), cardiac output (-0.2 ± 0.6 L/min vs -1.9 ± 0.6 L/min; P < .05), and right atrial pressure (1.0 ± 0.5 mm Hg vs -0.6 ± 0.5 mm Hg; P < .05) were greater in the pyridostigmine group compared with placebo. INTERPRETATION: Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03674541; URL: www. CLINICALTRIALS: gov.
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Syndrome de fatigue chronique , Humains , Syndrome de fatigue chronique/traitement médicamenteux , Bromure de pyridostigmine/usage thérapeutique , Exercice physique/physiologie , Épreuve d'effortRÉSUMÉ
Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m5C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m5C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m5C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the LSL-KrasG12D/+;Trp53fl/fl;Pdx1-Cre (KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant KrasG12D and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo. SIGNIFICANCE: Transcriptome-wide mRNA bisulfite sequencing identified candidate m5C sites of mRNAs in human pancreatic cancer cells. NSUN2-mediated m5C mRNA metabolism was observed in a mouse model of pancreatic cancer. NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.
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Carcinome du canal pancréatique , Tumeurs du pancréas , 5-Méthyl-cytosine , Animaux , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/anatomopathologie , Transformation cellulaire néoplasique/génétique , Modèles animaux de maladie humaine , Humains , Methyltransferases/métabolisme , Souris , Tumeurs du pancréas/génétique , Tumeurs du pancréas/anatomopathologie , Protéines proto-oncogènes p21(ras)/métabolisme , ARN , ARN messager/génétique , Sulfites , Tumeurs du pancréasRÉSUMÉ
Antimicrobial drug resistance is one of the major threats to global health. It has made common infections increasingly difficult or impossible to treat, and leads to higher medical costs, prolonged hospital stays and increased mortality. Infection rates due to multidrug-resistant organisms (MDRO) are increasing globally. Active agents against MDRO are limited despite an increased in the availability of novel antibiotics in recent years. This guideline aims to assist clinicians in the management of infections due to MDRO. The 2019 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group, comprising of infectious disease specialists from 14 medical centers in Taiwan, reviewed current evidences and drafted recommendations for the treatment of infections due to MDRO. A nationwide expert panel reviewed the recommendations during a consensus meeting in Aug 2020, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes recommendations for selecting antimicrobial therapy for infections caused by carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and vancomycin-resistant Enterococcus. The guideline takes into consideration the local epidemiology, and includes antimicrobial agents that may not yet be available in Taiwan. It is intended to serve as a clinical guide and not to supersede the clinical judgment of physicians in the management of individual patients.
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Acinetobacter baumannii , Entérocoques résistants à la vancomycine , Antibactériens/pharmacologie , Antibactériens/usage thérapeutique , Carbapénèmes , Multirésistance bactérienne aux médicaments , Humains , Tests de sensibilité microbienneRÉSUMÉ
Preoperative localization holds promise for overcoming the limitations of video-assisted thoracoscopic surgery (VATS) in the treatment of impalpable lung nodules. The purpose of this study was to assess the safety and efficacy of cone-beam computed tomography (CBCT)-guided localization using near-infrared (NIR) marking. Between 2017 and 2021, patients presenting with a solitary pulmonary nodule (SPN) who had undergone CBCT-guided lesion localization with indocyanine green (ICG) in a hybrid operating room were included. The primary outcomes were the efficacy of localization and the occurrence of complications. The study cohort consisted of 175 patients with the mean age of 58.76 years. The mean size and depth of the 175 SPNs were 8.34 mm and 5.3 mm, respectively. The mean time required for lesion marking was 14.71 min. Upon thoracoscopic inspection, the NIR tattoo was detected in the vast majority of the study participants (98.3%). An utility thoracotomy to allow digital palpation was required in two of the three patients in whom the tattoo was not identifiable. The perioperative survival rate was 100%, and the mean length of hospital stay was 3.09 days. We conclude that needle localization with ICG injection is a safe and feasible technique to localize SPNs prior to resection.
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Accidental out-of-hospital deliveries (OHDs) are known to have a higher incidence of maternal and neonatal complications. However, neonatal infection related to OHDs has not been studied. The aim of this study was to determine the infection risk of OHDs. This retrospective cohort study enrolled neonates admitted at a children's hospital in an urban setting from January 2004 to December 2017. Accidental OHDs were compared with in-hospital births, and neonatal infection was assessed. This study also investigated both maternal and neonatal risk factors associated with OHDs. A cohort of 158 OHD neonates was enrolled, of whom 29 (23.2%) were preterm. Prematurity and low birth weight were significantly associated with OHD. Eight neonates in the OHD cohort had a documented infection within the first 72 hours of life, which was 11-fold higher than infections documented for the in-hospital births. Multivariate analysis identified low birth weight as the only factor independently associated with increased risk of infection in OHD neonates. Several specific characteristics of mothers with OHDs were identified. Forty-nine (31%) OHD mothers lacked antenatal care, and 10 (6.3%) were unaware of their pregnancies. The OHD group comprised of more teenage mothers compared to the in-hospital deliveries category. Neonatal infection was more prevalent among OHDs than for in-hospital deliveries, and the infection rate was associated with low birth weight. Hospitalization for further care and observation is suggested for the OHD neonates. Social support should be provided for populations with an increased risk of OHD, such as teenage mothers.
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Maladies transmissibles/épidémiologie , Accouchement (procédure)/statistiques et données numériques , Maladies néonatales/épidémiologie , Maladies du prématuré/épidémiologie , Adolescent , Adulte , Accouchement (procédure)/effets indésirables , Femelle , Humains , Nourrisson à faible poids de naissance , Nouveau-né , Prématuré , Mâle , Âge maternel , Analyse multifactorielle , Prévalence , Études rétrospectives , Jeune adulteRÉSUMÉ
Despite vaccination, pancreas disease (PD) caused by salmonid alphavirus (SAV) has been the economically most important virus disease in salmon farming in Ireland, Scotland, and Norway. A vaccine based on DNA plasmid has been authorized to be used in Norwegian aquaculture since 2018. DNA vaccination of plasmids expressed subcellular viral proteins have been shown its particular protective effect against SAV3 that surface expression of the E2 protein with the whole viral protein construct, yielding a more effective vaccine. The chapter describes methods to design and test the sublocalization of expressed viral protein and the performance evaluation of vaccines against SAV3 infection in Atlantic salmon.
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Infections à alphavirus , Alphavirus , Maladies des poissons , Salmonidae , Vaccins à ADN , Alphavirus/génétique , Alphavirus/immunologie , Infections à alphavirus/prévention et contrôle , Infections à alphavirus/médecine vétérinaire , Animaux , Maladies des poissons/prévention et contrôle , Protéines viralesRÉSUMÉ
A triangular configuration with three parallel cannulated screws is an established treatment for fixing transverse patellar fractures; however, the stability achieved with this approach is slightly lower than that attained with cannulated screws combined with anterior wiring. In the present study, triangular configurations were modified by partially or totally replacing the cannulated screws with headless compression screws (HCSs). Through finite element simulation involving a model of distal femoral, patellar, and proximal tibial fractures, the mechanical stability levels of the modified triangular configurations were compared with that of two cannulated screws combined with anterior wiring. Four triangular screw configurations were developed: three HCSs in a forward and backward triangular configuration, two deep cannulated screws along with one superficial HCS, and two superficial cannulated screws with one deep HCS. Also considered were two parallel cannulated screws (inserted superficially or deeply) combined with anterior wiring. The six approaches were all examined in full knee extension and 45° flexion under physiological loading. The highest stability was obtained with the three HCSs in a backward triangular configuration, as indicated by the least fragment displacement and the smallest fracture gap size. In extension and flexion, this size was smaller than that observed under the use of two deeply placed parallel cannulated screws with anterior wiring by 50.3% (1.53 vs. 0.76 mm) and 43.2% (1.48 vs. 0.84 mm), respectively. Thus, the use of three HCSs in a backward triangular configuration is recommended for the fixation of transverse patellar fractures, especially without the use of anterior wiring.
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Vis orthopédiques , Fractures osseuses , Phénomènes biomécaniques , Ostéosynthèse interne , Fractures osseuses/chirurgie , Humains , Patella/chirurgie , Amplitude articulaireRÉSUMÉ
One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls. The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments. Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.
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The primary goal of the unrelated population HLA diversity (UPHD) component of the 17th International HLA and Immunogenetics Workshop was to characterize HLA alleles at maximum allelic-resolution in worldwide populations and re-evaluate patterns of HLA diversity across populations. The UPHD project included HLA genotype and sequence data, generated by various next-generation sequencing methods, from 4,240 individuals collated from 12 different countries. Population data included well-defined large datasets from the USA and smaller samples from Europe, Australia, and Western Asia. Allele and haplotype frequencies varied across populations from distant geographical regions. HLA genetic diversity estimated at 2- and 4-field allelic resolution revealed that diversity at the majority of loci, particularly for European-descent populations, was lower at the 2-field resolution. Several common alleles with identical protein sequences differing only by intronic substitutions were found in distinct haplotypes, revealing a more detailed characterization of linkage between variants within the HLA region. The examination of coding and non-coding nucleotide variation revealed many examples in which almost complete biunivocal relations between common alleles at different loci were observed resulting in higher linkage disequilibrium. Our reference data of HLA profiles characterized at maximum resolution from many populations is useful for anthropological studies, unrelated donor searches, transplantation, and disease association studies.
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Allèles , Fréquence d'allèle , Génétique des populations , Antigènes HLA/génétique , Haplotypes , Séquençage nucléotidique à haut débit , Immunogénétique , Prédisposition aux maladies , Études d'associations génétiques , Génétique des populations/méthodes , Humains , Immunogénétique/méthodes , Immunologie en transplantationRÉSUMÉ
BACKGROUND: Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. RESULTS: All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. CONCLUSION: This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.
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Marqueurs biologiques tumoraux , Dépistage génétique/méthodes , Génomique/méthodes , Tumeurs/génétique , Oncogènes , Variations de nombre de copies de segment d'ADN , Dépistage génétique/normes , Génomique/normes , Humains , Techniques de diagnostic moléculaire/méthodes , Techniques de diagnostic moléculaire/normes , Mutation , Tumeurs/diagnostic , Polymorphisme de nucléotide simple , Reproductibilité des résultats , Sensibilité et spécificitéRÉSUMÉ
BACKGROUND: Oncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance. RESULTS: In reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100× more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels. CONCLUSION: These new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.