6,626 research outputs found
Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis.
Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy
Pathological and normal variability of foot bones in osteological collections from Catalonia (Spain) and Lazio (Italy)
A wide number of factors can affect the structure of the bones in the foot. In bioarchaeology, few studies about foot anomalies include population comparisons and
changes across time. We aimed to identify normal and pathological variability that
affected the foot in the recent history of West Mediterranean populations. Thus, we
analyzed change in occurrence of rare variants, pathological lesions, entheseal morphology, and their probable causes. We studied 518 pairs of skeletonized feet dated
from the 2ndâ20th centuries CE, from Catalonia (Spain) and the region of Lazio
(Italy). Moreover, a Neolithic series from Oman has been analyzed for contrast. We
found that calcaneal spur, hypertrophic peroneal trochlea of calcaneus, periosteal
reaction of talar neck, alteration of articular surface to lateral cuneiform, displaced
talar neck to medial plane, osteophytes in cuneiform-navicular joint, fused phalanges,
and forefoot eburnation showed significant differences among countries. Contrasting
by countries and dates, we noticed an increase in the frequencies of these variables
from Spain over the centuries. Conversely, there are no temporal differences among
the Italian series. The period encompassing the 10thâ19th centuries CE demonstrated the highest differences between countries. Lifestyle, occupations, footwear,
and geography could be the origin of variability
Recent Technological Developments on LGAD and iLGAD Detectors for Tracking and Timing Applications
This paper reports the last technological development on the Low Gain
Avalanche Detector (LGAD) and introduces a new architecture of these detectors
called inverse-LGAD (iLGAD). Both approaches are based on the standard
Avalanche Photo Diodes (APD) concept, commonly used in optical and X-ray
detection applications, including an internal multiplication of the charge
generated by radiation. The multiplication is inherent to the basic n++-p+-p
structure, where the doping profile of the p+ layer is optimized to achieve
high field and high impact ionization at the junction. The LGAD structures are
optimized for applications such as tracking or timing detectors for high energy
physics experiments or medical applications where time resolution lower than 30
ps is required. Detailed TCAD device simulations together with the electrical
and charge collection measurements are presented through this work.Comment: Keywords: silicon detectors, avalanche multiplication, timing
detectors, tracking detectors. 8 pages. 8 Figure
Biochemicalâmolecularâgenetic biomarkers in the tear film, aqueous humor, and blood of primary open-angle glaucoma patients
Introduction: Glaucoma is a chronic neurodegenerative disease, which is the leading cause of irreversible blindness worldwide. As a response to high intraocular pressure, the clinical and molecular glaucoma biomarkers indicate the biological state of the visual system. Classical and uncovering novel biomarkers of glaucoma development and progression, follow-up, and monitoring the response to treatment are key objectives to improve vision outcomes. While the glaucoma imaging field has successfully validated biomarkers of disease progression, there is still a considerable need for developing new biomarkers of early glaucoma, that is, at the preclinical and initial glaucoma stages. Outstanding clinical trials and animal-model study designs, innovative technology, and analytical approaches in bioinformatics are essential tools to successfully uncover novel glaucoma biomarkers with a high potential for translation into clinical practice. Methods: To better understand the clinical and biochemical-molecular-genetic glaucoma pathogenesis, we conducted an analytical, observational, and case-comparative/control study in 358 primary open-angle glaucoma (POAG) patients and 226 comparative-control individuals (CG) to collect tears, aqueous humor, and blood samples to be processed for identifying POAG biomarkers by exploring several biological pathways, such as inflammation, neurotransmitter/neurotrophin alteration, oxidative stress, gene expression, miRNAs fingerprint and its biological targets, and vascular endothelial dysfunction, Statistics were done by using the IBM SPSS 25.0 program. Differences were considered statistically significant when p †0.05. Results: Mean age of the POAG patients was 70.03 ± 9.23 years, and 70.62 ± 7.89 years in the CG. Malondialdehyde (MDA), nitric oxide (NO), interleuquin (IL)-6, endothelin-1 (ET-1), and 5 hydroxyindolacetic acid (5-HIAA), displayed significantly higher levels in the POAG patients vs. the CG (p < 0.001). Total antioxidant capacity (TAC), brain derived neurotrophic factor (BDNF), 5-hydroxy tryptamine (5-HT), solute carrier family 23-nucleobase transporters-member 2 (SLC23A2) gene, and the glutathione peroxidase 4 (GPX4) gene, showed significantly lower levelsin the POAG patients than in the CG (p < 0.001). The miRNAs that differentially expressed in tear samples of the POAG patients respect to the CG were the hsa miR-26b-5p (involved in cell proliferation and apoptosis), hsa miR-152-3p (regulator of cell proliferation, and extracellular matrix expression), hsa miR-30e-5p (regulator of autophagy and apoptosis), and hsa miR-151a-3p (regulator of myoblast proliferation). Discussion: We are incredibly enthusiastic gathering as much information as possible on POAG biomarkers to learn how the above information can be used to better steer the diagnosis and therapy of glaucoma to prevent blindness in the predictable future. In fact, we may suggest that the design and development of blended biomarkers is a more appropriate solution in ophthalmological practice for early diagnosis and to predict therapeutic response in the POAG patients
Study of vascular risk in Navarre: objectives and design. Prevalence of metabolic syndrome and of vascular risk factors
BACKGROUND: To determine in a representative sample of the population the prevalence of risk factors and metabolic syndrome; their association with sub-clinical atherosclerotic lesions and their impact on cardiocerebrovascular disease 10 years after.
MATERIAL AND METHODS: (Phase 1) Cross sectional survey of a random sample stratified by age and sex of the population of Navarre aged between 35 and 84. Antecedents, risk factors, physical and analytical exploration. (Phase II) Ten year follow-up cohort study, in 500 exposed to MS and 500 not exposed persons, aged between 45 and 74 years; with an 82.25% power to detect a risk ratio of 2; with analytical and image markers of sub-clinical atherosclerosis. (Phase III) Follow up of vascular events at ten years.
RESULTS: The subjects recruited were 6,553; excluded or not found 871; the final sample was 5,682 (2,644 men and 3,038 women); 4,168 (73,4%) took part in the study. The prevalence of MS was 22.1% (95%CI 20.5 - 23.7) for men and 17,2% (95%CI 15.8 - 18.5) for women. The main cardiovascular RF were high compared to other geographical areas except for HDL cholesterol. The rate was 8.5% (95%CI 7.4 - 9.6) for men and 1.7% (95%CI 1.3 - 2.2)
CONCLUSIONS: There are important differences in risk between sex, being worst for men. The high figures for HDL cholesterol and the low prevalence of MS might mean a lower risk of vascular events in Navarra
Usefulness of two independent DNA and rna tissue-based multiplex assays for the routine care of advanced NSCLC patients
Personalized medicine is nowadays a paradigm in lung cancer management, offering important benefits to patients. This study aimed to test the feasibility and utility of embedding two multiplexed genomic platforms as the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Two parallel multiplexed approaches were performed based on DNA sequencing and direct digital detection of RNA with nCounterÂź technology to evaluate gene mutations and fusions. The results were used to guide genotype-directed therapies and patient outcomes were collected. A total of 224 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 85% of samples were successfully characterized at DNA and RNA levels and oncogenic drivers were found in 68% of patients, with KRAS, EGFR, METâex14, BRAF, and ALK being the most frequent (31%, 19%, 5%, 4%, and 4%, respectively). Among all patients with complete genotyping results and follow-up data (n = 156), the median overall survival (OS) was 1.90 years (confidence interval (CI) 95% 1.69-2.10) for individuals harbouring an actionable driver treated with a matched therapy, compared with 0.59 years (CI 95% 0.39-0.79) in those not eligible for any targeted therapy and 0.61 years (CI 95% 0.12-1.10) in patients with no drivers identified (p < 0.001). Integrating DNA and RNA multiplexing technologies into the routine molecular testing of advanced NSCLC patients is feasible and useful and highlights the necessity of widespread integrating comprehensive molecular diagnosis into lung cancer care
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White matter hyperintensities are a prominent feature of autosomal dominant Alzheimerâs disease that emerge prior to dementia
Background
To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimerâs disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimerâs disease, in relation to age and symptom severity.
Methods
This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimerâs Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55Â years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.
Results
The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43Â years, 1Â year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.
Conclusions
The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimerâs disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimerâs disease that is closely related to the progression of clinical symptoms
Natural immunity to SARS-CoV-2 and breakthrough infections in vaccinated and unvaccinated patients with cancer
Background Consolidated evidence suggests spontaneous immunity from SARS-CoV-2 is not durable, leading to the risk of reinfection, especially in the context of newly emerging viral strains. In patients with cancer who survive COVID-19 prevalence and severity of SARS-CoV-2 reinfections are unknown. Methods We aimed to document natural history and outcome from SARS-CoV-2 reinfection in patients recruited to OnCovid (NCT04393974), an active European registry enrolling consecutive patients with a history of solid or haematologic malignancy diagnosed with COVID-19. Results As of December 2021, out of 3108 eligible participants, 1806 COVID-19 survivors were subsequently followed at participating institutions. Among them, 34 reinfections (1.9%) were reported after a median time of 152 days (range: 40â620) from the first COVID-19 diagnosis, and with a median observation period from the second infection of 115 days (95% CI: 27â196). Most of the first infections were diagnosed in 2020 (27, 79.4%), while most of reinfections in 2021 (25, 73.5%). Haematological malignancies were the most frequent primary tumour (12, 35%). Compared to first infections, second infections had lower prevalence of COVID-19 symptoms (52.9% vs 91.2%, Pâ=â0.0008) and required less COVID-19-specific therapy (11.8% vs 50%, Pâ=â0.0013). Overall, 11 patients (32.4%) and 3 (8.8%) were fully and partially vaccinated against SARS-CoV-2 before the second infection, respectively. The 14-day case fatality rate was 11.8%, with four death events, none of which among fully vaccinated patients. Conclusion This study shows that reinfections in COVID-19 survivors with cancer are possible and more common in patients with haematological malignancies. Reinfections carry a 11% risk of mortality, which rises to 15% among unvaccinated patients, highlighting the importance of universal vaccination of patients with cancer
Study of CP violation in Dalitz-plot analyses of B0 --> K+K-KS, B+ --> K+K-K+, and B+ --> KSKSK+
We perform amplitude analyses of the decays , , and , and measure CP-violating
parameters and partial branching fractions. The results are based on a data
sample of approximately decays, collected with the
BABAR detector at the PEP-II asymmetric-energy factory at the SLAC National
Accelerator Laboratory. For , we find a direct CP asymmetry
in of , which differs
from zero by . For , we measure the
CP-violating phase .
For , we measure an overall direct CP asymmetry of
. We also perform an angular-moment analysis of
the three channels, and determine that the state can be described
well by the sum of the resonances , , and
.Comment: 35 pages, 68 postscript figures. v3 - minor modifications to agree
with published versio
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