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1.
ACS Biomater Sci Eng ; 8(1): 119-127, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34908395

RESUMO

Spider flagelliform silk shows the best extensibility among various types of silk, but its biomimetic preparation has not been much studied. Herein, five customized flagelliform spidroins (FlSps: S and NTDFl-Sn-CTDFl, n = 1-4), in which the repetitive region (S) and N-/C- terminal domains (NTDFl and CTDFl) are from the same spidroin and spider species, were produced recombinantly. The recombinant spidroins with terminal domains were able to form silk-like fibers with diameters of ∼5 µm by manual pulling at pH 8.0, where the secondary structure transformation occurred. The silk-like fibers from NTDFl-S4-CTDFl showed the highest tensile strength (∼250 MPa), while those ones with 1-3 S broke at a similar stress (∼180 MPa), suggesting that increasing the amounts of the repetitive region can improve the tensile strength, but a certain threshold might need to be reached. This study shows successful preparation of flagelliform silk-like fibers with good mechanical properties, providing general insights into efficient biomimetic preparations of spider silks.

2.
Proc Natl Acad Sci U S A ; 118(52)2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34949639

RESUMO

A growing list of Alzheimer's disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP Our data also show that ROS enhances Aß42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.

3.
Sci Rep ; 11(1): 21069, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702933

RESUMO

AA amyloidosis can be transmitted experimentally in several mammalian and avian species as well as spontaneously between captive animals, even by oral intake of amyloid seeds. Amyloid seeding can cross species boundaries, and fibrils of one kind of amyloid protein may also seed other types. Here we show that meat from Swedish and Italian cattle for consumption by humans often contains AA amyloid and that bovine AA fibrils efficiently cross-seed human amyloid ß peptide, associated with Alzheimer's disease.

4.
FASEB J ; 35(11): e21896, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34634154

RESUMO

Surgical intervention with the use of autografts is considered the gold standard to treat peripheral nerve injuries. However, a biomaterial that supports and guides nerve growth would be an attractive alternative to overcome problems with limited availability, morbidity at the site of harvest, and nerve mismatches related to autografts. Native spider silk is a promising material for construction of nerve guidance conduit (NGC), as it enables regeneration of cm-long nerve injuries in sheep, but regulatory requirements for medical devices demand synthetic materials. Here, we use a recombinant spider silk protein (NT2RepCT) and a functionalized variant carrying a peptide derived from vitronectin (VN-NT2RepCT) as substrates for nerve growth support and neurite extension, using a dorsal root ganglion cell line, ND7/23. Two-dimensional coatings were benchmarked against poly-d-lysine and recombinant laminins. Both spider silk coatings performed as the control substrates with regards to proliferation, survival, and neurite growth. Furthermore, NT2RepCT and VN-NT2RepCT spun into continuous fibers in a biomimetic spinning set-up support cell survival, neurite growth, and guidance to an even larger extent than native spider silk. Thus, artificial spider silk is a promising biomaterial for development of NGCs.


Assuntos
Proliferação de Células/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Neuritos/metabolismo , Seda/farmacologia , Aranhas/metabolismo , Vitronectina/farmacologia , Animais , Autoenxertos , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Gânglios Espinais/citologia , Humanos , Laminina/farmacologia , Camundongos , Neuritos/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/cirurgia , Engenharia de Proteínas/métodos , Ratos , Proteínas Recombinantes/farmacologia , Seda/genética , Vitronectina/genética
6.
Neurobiol Dis ; 159: 105514, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34555537

RESUMO

Synchronized and properly balanced electrical activity of neurons is the basis for the brain's ability to process information, to learn, and to remember. In Alzheimer's disease (AD), which causes cognitive decline in patients, this synchronization and balance is disturbed by the accumulation of neuropathological biomarkers such as amyloid-beta peptide (Aß42). Failure of Aß42 clearance mechanisms as well as desynchronization of crucial neuronal classes such as fast-spiking interneurons (FSN) are root causes for the disruption of the cognition-relevant gamma brain rhythm (30-80 Hz) and consequent cognitive impairment observed in AD. Here we show that recombinant BRICHOS molecular chaperone domains from ProSP-C or Bri2, which interfere with Aß42 aggregation, can rescue the gamma rhythm. We demonstrate that Aß42 progressively decreases gamma oscillation power and rhythmicity, disrupts the inhibition/excitation balance in pyramidal cells, and desynchronizes FSN firing during gamma oscillations in the hippocampal CA3 network of mice. Application of the more efficacious Bri2 BRICHOS chaperone rescued the cellular and neuronal network performance from all ongoing Aß42-induced functional impairments. Collectively, our findings offer critical missing data to explain the importance of FSN for normal network function and underscore the therapeutic potential of Bri2 BRICHOS to rescue the disruption of cognition-relevant brain rhythms in AD.

7.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359882

RESUMO

Scaffolds of recombinant spider silk protein (spidroin) and hyaluronic acid (HA) hydrogel hold promise in combination with cell therapy for spinal cord injury. However, little is known concerning the human immune response to these biomaterials and grafted human neural stem/progenitor cells (hNPCs). Here, we analyzed short- and long-term in vitro activation of immune cells in human peripheral blood mononuclear cells (hPBMCs) cultured with/without recombinant spidroins, HA hydrogels, and/or allogeneic hNPCs to assess potential host-donor interactions. Viability, proliferation and phenotype of hPBMCs were analyzed using NucleoCounter and flow cytometry. hPBMC viability was confirmed after exposure to the different biomaterials. Short-term (15 h) co-cultures of hPBMCs with spidroins, but not with HA hydrogel, resulted in a significant increase in the proportion of activated CD69+ CD4+ T cells, CD8+ T cells, B cells and NK cells, which likely was caused by residual endotoxins from the Escherichia coli expression system. The observed spidroin-induced hPBMC activation was not altered by hNPCs. It is resource-effective to evaluate human compatibility of novel biomaterials early in development of the production process to, when necessary, make alterations to minimize rejection risk. Here, we present a method to evaluate biomaterials and hPBMC compatibility in conjunction with allogeneic human cells.


Assuntos
Fibroínas/farmacologia , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Aborto Legal , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Encapsulamento de Células/métodos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Feto , Fibroínas/química , Humanos , Ácido Hialurônico/química , Hidrogéis/química , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Modelos Biológicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/imunologia , Gravidez , Primeiro Trimestre da Gravidez , Cultura Primária de Células , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Medula Espinal/citologia , Medula Espinal/imunologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
8.
J Alzheimers Dis ; 83(4): 1703-1715, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34459400

RESUMO

BACKGROUND: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. OBJECTIVE: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). METHODS: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. RESULTS: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). CONCLUSION: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

9.
Ther Adv Med Oncol ; 13: 17588359211027837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262618

RESUMO

Aims: The role of resection remains debated in cases of metastatic gastric carcinoma (mGC). Some mGCs are technically resectable. At the population level, the real-world application of resection for mGC remains largely unclear in most Western countries. This large, population-based international investigation aimed to reveal the resection patterns and trends for mGC and the treatment-associated factors in Europe and the US. Methods: Data on cases with microscopically-confirmed primary invasive stomach carcinoma with distant metastasis were obtained from the nationwide cancer registries of the Netherlands, Belgium, Norway, Sweden, Estonia, and Slovenia and the US Surveillance, Epidemiology, and End Results-18 database. We calculated age-standardized rates of primary cancer-directed resection and assessed resection trends using linear regression. We investigated associations of treatment with patient and cancer factors using multivariable-adjusted log-binomial regression. Results: Among 133,321 patients with gastric cancer, overall, 40,215 cases with mGC diagnosed between 2003-2017 were investigated. Age-standardized resection rates significantly declined over time in the US, Belgium, Sweden, and Norway (by 5-14%). Resection rates greatly differed from 5% to 16% in 2013-2014. Cases with older ages, cardia tumors, or tumors involving adjacent structures were significantly less often operated across most countries. Sex was not significantly associated with resection. Across countries the association patterns and strengths differed largely. With multivariable adjustment, resection rates decreased significantly in all countries except Slovenia and Estonia (prevalence ratio per year = 0.90-0.98), and the decreasing trends were consistently observed in various stratifications by age and location. Conclusion: In Europe and the US, resection patterns and trends largely varied across countries for mGCs, which were mostly less often resected in the early 21st century. Various resection-associated factors were shown, with greatly varying association patterns and strengths. Our report could aid to identify discrepancies in clinical practice and highlight the great need for further clarifying the role of resection in mGCs to enhance standardization of care.

10.
Microb Cell Fact ; 20(1): 150, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330289

RESUMO

BACKGROUND: The human Bri2 BRICHOS domain inhibits amyloid formation and toxicity and could be used as a therapeutic agent against amyloid diseases. For translation into clinical use, large quantities of correctly folded recombinant human (rh) Bri2 BRICHOS are required. To increase the expression and solubility levels of rh Bri2 BRICHOS it was fused to NT*, a solubility tag derived from the N-terminal domain of a spider silk protein, which significantly increases expression levels and solubility of target proteins. To increase the expression levels even further and reach the g/L range, which is a prerequisite for an economical production on an industrial scale, we developed a fed-batch expression protocol for Escherichia coli. RESULTS: A fed-batch production method for NT*-Bri2 BRICHOS was set up and systematically optimized. This gradual improvement resulted in expression levels of up to 18.8 g/L. Following expression, NT*-Bri2 BRICHOS was purified by chromatographic methods to a final yield of up to 6.5 g/L. After removal of the NT*-tag and separation into different oligomeric species, activity assays verified that different assembly states of the fed-batch produced rh Bri2 BRICHOS have the same ability to inhibit fibrillar and non-fibrillar protein aggregation as the reference protein isolated from shake flask cultures. CONCLUSIONS: The protocol developed in this work allows the production of large quantities of rh Bri2 BRICHOS using the solubility enhancing NT*-tag as a fusion partner, which is required to effectively conduct pre-clinical research.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Técnicas de Cultura Celular por Lotes/métodos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Chaperonas Moleculares/genética , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Proteínas Recombinantes/metabolismo
11.
J Immunol ; 207(3): 974-984, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34282000

RESUMO

K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide. Peptidylarginine deiminases (PAD) convert cationic peptidyl arginine to neutral citrulline. Thus, we hypothesized that citrullination is a biologically relevant modification of the peptide that would reduce the antibacterial and LPS-binding activities of K9CATH. Recombinant PAD2 and PAD4 citrullinated K9CATH to various extents and circular dichroism spectroscopy revealed that both native and citrullinated K9CATH exhibited similar α-helical secondary structures. Notably, citrullination of K9CATH reduced its bactericidal activity, abolished its ability to permeabilize the membrane of Gram-negative bacteria and reduced the hemolytic capacity. Electron microscopy showed that citrullinated K9CATH did not cause any morphological changes of Gram-negative bacteria, whereas the native peptide caused clear alterations of membrane integrity, concordant with a rapid bactericidal effect. Finally, citrullination of K9CATH impaired its capacity to inhibit LPS-mediated release of proinflammatory molecules from mouse and canine macrophages. In conclusion, citrullination attenuates the antibacterial and the LPS-binding properties of K9CATH, demonstrating the importance of a net positive charge for antibacterial lysis of bacteria and LPS-binding effects and suggests that citrullination is a means to regulate cathelicidin activities.


Assuntos
Antibacterianos/metabolismo , Anti-Inflamatórios/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Infecções por Escherichia coli/imunologia , Escherichia coli/fisiologia , Macrófagos/imunologia , Infecções por Pasteurella/metabolismo , Pasteurella multocida/fisiologia , Desiminases de Arginina em Proteínas/metabolismo , Animais , Antibacterianos/química , Anti-Inflamatórios/química , Peptídeos Catiônicos Antimicrobianos/química , Citrulinação , Cães , Imunidade Inata , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Ligação Proteica , Células RAW 264.7
12.
Cardiovasc Diabetol ; 20(1): 125, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158057

RESUMO

BACKGROUND: In stable patients with type 2 diabetes (T2D), insulin treatment is associated with elevated risk for major adverse cardiovascular events (MACE). Patients with acute coronary syndrome (ACS) and T2D are at particularly high risk for recurrent MACE despite evidence-based therapies. It is uncertain to what extent this risk is further magnified in patients with recent ACS who are treated with insulin. We examined the relationship of insulin use to risk of MACE and modification of that risk by apabetalone, a bromodomain and extra-terminal (BET) protein inhibitor. METHODS: The analysis utilized data from the BETonMACE phase 3 trial that compared apabetalone to placebo in patients with T2D, low HDL cholesterol, andACS. The primary MACE outcome (cardiovascular death, myocardial infarction, or stroke) was examined according to insulin treatment and assigned study treatment. Multivariable Cox regression was used to determine whether insulin use was independently associated with the risk of MACE. RESULTS: Among 2418 patients followed for median 26.5 months, 829 (34.2%) were treated with insulin. Despite high utilization of evidence-based treatments including coronary revascularization, intensive statin treatment, and dual antiplatelet therapy, the 3-year incidence of MACE in the placebo group was elevated among insulin-treated patients (20.4%) compared to those not-treated with insulin (12.8%, P = 0.0001). Insulin treatment remained strongly associated with the risk of MACE (HR 2.10, 95% CI 1.42-3.10, P = 0.0002) after adjustment for demographic, clinical, and treatment variables. Apabetalone had a consistent, favorable effect on MACE in insulin-treated and not insulin-treated patients. CONCLUSION: Insulin-treated patients with T2D, low HDL cholesterol, and ACS are at high risk for recurrent MACE despite the use of evidence-based, contemporary therapies. A strong association of insulin treatment with risk of MACE persists after adjustment for other characteristics associated with MACE. There is unmet need for additional treatments to mitigate this risk. Trial registration ClinicalTrials.gov NCT02586155, registered October 26, 2015.

13.
Ann Surg ; 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34183514

RESUMO

OBJECTIVE: To examine the hypothesis that survival in esophageal cancer increases with more removed lymph nodes during esophagectomy up to a plateau, after which it levels out or even decreases with further lymphadenectomy. SUMMARY BACKGROUND DATA: There is uncertainty regarding the ideal extent of lymphadenectomy during esophagectomy to optimize long-term survival in esophageal cancer. METHODS: This population-based cohort study included almost every patient who underwent esophagectomy for esophageal cancer in Sweden or Finland in 2000-2016 with follow-up through 2019. Degree of lymphadenectomy, divided into deciles, was analyzed in relation to all-cause 5-year mortality. Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for all established prognostic factors. RESULTS: Among 2,306 patients, the 2nd (4-8 nodes), 7th (21-24 nodes) and 8th decile (25-30 nodes) of lymphadenectomy showed the lowest all-cause 5-year mortality compared to the 1st decile (HR = 0.77, 95% CI 0.61-0.97, HR = 0.76, 95% CI 0.59-0.99, and HR = 0.73, 95% CI 0.57-0.93, respectively). In stratified analyses, the survival benefit was greatest in decile 7 for patients with pathological T-stage T3/T4 (HR = 0.56, 95% CI 0.40-0.78), although it was statistically improved in all deciles except decile 10. For patients without neoadjuvant chemotherapy, survival was greatest in decile 7 (HR = 0.60, 95% CI 0.41-0.86), although survival was also statistically significantly improved in deciles 2, 6, and 8. CONCLUSION: Survival in esophageal cancer was not improved by extensive lymphadenectomy, but resection of a moderate number (20-30) of nodes was prognostically beneficial for patients with advanced T-stages (T3/T4) and those not receiving neoadjuvant therapy.

14.
J Rehabil Med ; 53(7): jrm00213, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34037240

RESUMO

OBJECTIVE: To evaluate the feasibility of using a wearable eye-tracker when assessing patients with prolonged disorders of consciousness using the Coma Recovery Scale Revised (CRS-R), focusing on technical challenges. DESIGN: A methodological investigation with descriptive and analytical elements. SUBJECTS: Four patients with prolonged disorders of consciousness were recruited from the rehabilitation clinic of a regional rehabilitation unit. METHODS: A selection of subtests in the CRS-R were performed while recording eye movements with a wearable eye-tracker. RESULTS: No major adverse reactions were observed, suggesting likely patient acceptability. Calibration was not always possible. However, distinct eye movements were discernible from the recorded data even without calibration, and analysis of these produced results with the potential to support clinical assessment. CONCLUSION: Eye tracking was feasible during clinical assessment for this patient group. Recording eye movement responses in these easily fatigued patients has the potential to add sensitivity for detection of conscious responses and to complement clinical examination. Further study is merited. Current hardware and software limitations can be overcome with manual data processing and analysis; however, significant developments in automating data processing will be required for broader clinical application.


Assuntos
Transtornos da Consciência/diagnóstico , Tecnologia de Rastreamento Ocular , Dispositivos Eletrônicos Vestíveis , Adulto , Tecnologia de Rastreamento Ocular/efeitos adversos , Estudos de Viabilidade , Humanos , Escala de Gravidade do Ferimento , Satisfação do Paciente , Dispositivos Eletrônicos Vestíveis/efeitos adversos , Adulto Jovem
15.
J Med Case Rep ; 15(1): 223, 2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-33933141

RESUMO

BACKGROUND: Effort rupture of the esophagus or Boerhaave's syndrome is a rare entity, and prognosis is largely dependent on early diagnosis and treatment. Recurrent effort ruptures are very rare, only reported in a few case reports in English literature. We present a case with a third time effort rupture, and to the best of our knowledge there are no such previous publications. Furthermore, the presented case is also distinct because each episode was treated by different methods, reflecting the pathophysiology of recurrent disease as well as the last decade's advancements in the management of esophageal perforations in our clinic and globally. CASE PRESENTATION: The patient is a 60-year-old White male, suffering from alcohol abuse, mild reflux esophagitis, and a history of effort esophageal ruptures on two previous occasions. He was now admitted to our ward once again because of a third bout of Boerhaave's syndrome. The first time, 10 years ago, he was managed by thoracotomy and laparotomy with primary repair, and the second time, 5 years ago, by transhiatal mediastinal drainage through a laparotomy and endoscopic stent placement. Now he was successfully managed by endovascular vacuum-assisted closure therapy alone. CONCLUSIONS: Recurrent cases of Boerhaave's syndrome are very rare, and treatment must be tailored individually. The basic rationale is, however, no different from primary disease: (1) early diagnosis, (2) adequate drainage of extraesophageal contamination, and (3) restoration of esophageal integrity. Recurrent disease is usually contained and exceptionally suitable for primary endoscopic treatment. To cover the full panorama and difficult nature of complex esophageal disease, endoscopic modalities such as stent placement and endovascular vacuum-assisted closure, as well as the capacity for prompt extensive surgical interventions such as esophagectomy, should be readily accessible within every modern esophageal center.


Assuntos
Perfuração Esofágica , Doenças do Mediastino , Drenagem , Perfuração Esofágica/diagnóstico por imagem , Perfuração Esofágica/cirurgia , Humanos , Masculino , Doenças do Mediastino/diagnóstico por imagem , Doenças do Mediastino/cirurgia , Pessoa de Meia-Idade , Ruptura Espontânea
16.
Sensors (Basel) ; 21(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804581

RESUMO

The tenth launch (L10) of the European Global Navigation Satellite System Galileo filled in all orbital slots in the constellation. The launch carried four Galileo satellites and took place in July 2018. The satellites were declared operational in February 2019. In this study, we report on the performance of the Galileo L10 satellites in terms of orbital inclination and repeat period parameters, broadcast satellite clocks and signal in space (SiS) performance indicators. We used all available broadcast navigation data from the IGS consolidated navigation files. These satellites have not been reported in the previous studies. First, the orbital inclination (56.7±0.15°) and repeat period (50680.7±0.22 s) for all four satellites are within the nominal values. The data analysis reveals also 13.5-, 27-, 177- and 354-days periodic signals. Second, the broadcast satellite clocks show different correction magnitude due to different trends in the bias component. One clock switch and several other minor correction jumps have occurred since the satellites were declared operational. Short-term discontinuities are within ±1 ps/s, whereas clock accuracy values are constantly below 0.20 m (root-mean-square-rms). Finally, the SiS performance has been very high in terms of availability and accuracy. Monthly SiS availability has been constantly above the target value of 87% and much higher in 2020 as compared to 2019. Monthly SiS accuracy has been below 0.20 m (95th percentile) and below 0.40 m (99th percentile). The performance figures depend on the content and quality of the consolidated navigation files as well as the precise reference products. Nevertheless, these levels of accuracy are well below the 7 m threshold (95th percentile) specified in the Galileo service definition document.

17.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811809

RESUMO

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.


Assuntos
COVID-19/complicações , Cardiotônicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Cardiopatias/tratamento farmacológico , Quinazolinonas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocinas/metabolismo , Feminino , Cardiopatias/etiologia , Células-Tronco Embrionárias Humanas , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/metabolismo
18.
Surg Endosc ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835253

RESUMO

BACKGROUND: Anastomotic leakage after esophagectomy is a serious and demanding complication. Early detection and treatment can probably prevent clinical deterioration of the patient. We have used early endoscopic assessment and a novel endoscopy score to predict anastomotic complications. METHODS: 57 patients planned for Ivor Lewis esophagectomy were included. Endoscopy videos were recorded and biopsies were taken from the gastric conduit on day 7 or 8 after esophagectomy. A scoring system based on the endoscopic appearance, the combined endoscopy score (0-6), was developed. Scoring of the videos was done blinded. Patient outcome with regards to anastomotic complications was registered on postoperative day 30 in accordance with the ECCG definitions and compared to histopathology assessment and the combined endoscopy score retrospectively. RESULTS: The rate of anastomotic defect (necrosis and leakage, ECCG definitions) was 19%. 7 out of 8 patients with a combined endoscopy score of ≥ 4 developed anastomotic defects. The combined endoscopy score was the only predictor for anastomotic complications. CONCLUSION: Prediction of anastomotic complications enables early detection and treatment which often limits the clinical extent of the complication. Early postoperative endoscopy is safe and a relatively simple procedure. The combined endoscopy score is an accurate tool to predict anastomotic complications.

19.
Transl Psychiatry ; 11(1): 212, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837176

RESUMO

Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75NTR). p75NTR mediates both apoptosis and survival and its expression is increased in Alzheimer's disease (AD) patients. Here, we investigate the importance of p75NTR for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75NTR knockout mice (p75-/-) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75-/- mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75NTR counteracts the Aß-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75NTR signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75NTR in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75NTR as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.


Assuntos
Ritmo Gama , Ritmo Teta , Animais , Hipocampo , Humanos , Camundongos , Camundongos Knockout , Neurônios
20.
Biomedicines ; 9(4)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919584

RESUMO

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

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