The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of ...oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N
-methyladenosine (m
A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m
A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m
A and the m
A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m
A that contributes to the integrated stress response of oTau.
Six different carbon-supported Cu core Pt–Pd shell (Cu@Pt–Pd) catalysts have been successfully synthesized by the galvanic replacement of Cu atoms by Pt4+ and Pd2+ ions at room temperature and their ...electrocatalytic activity for methanol and ethanol oxidation have been evaluated in acid media. Cu@Pt–Pd core shell nanoparticles with a narrow size distribution and an average diameter in the range of 3.1–3.5 nm were generated onto the carbon support. The compositional and the structural analysis of the as-prepared materials pointed out that the nanoparticles are formed by a Cu rich core covered by a Pt–Pd rich shell due to the interdiffusion of the metals after the galvanic replacement reaction. The electrocatalytic properties of the Cu@Pt–Pd electrodes in the electro-oxidation of methanol and ethanol was found to be dependent on the electrochemical surface area, lattice strain of the surface, composition and thickness of the Pt–Pd shell surrounding the Cu core. The optimum catalyst composition to obtain the best performance for methanol and ethanol electro-oxidation was determined to be Pt0.59Pd0.324Cu0.167/C (6.2 wt.% Pt, 2.2 wt.% Pd and 0.7 wt.% Cu). This catalyst has a greatly enhanced mass activity, lower onset potential and poisoning rate, and higher turnover number in the MOR and EOR reactions compared to a commercial Pt0.51Ru0.49/C (20 wt.% Pt and 10 wt.% Ru). Consequently, this simple preparation method is a viable approach to making a highly active catalyst with low platinum content for application in direct alcohol fuel cells (DAFCs).
•Carbon-supported Cu@Pt–Pd core–shell catalysts were prepared by redox replacement.•Nanoparticles of ∼3 nm were obtained and ECSA values from 40 to 136 m2 g−1 were measured.•Cu@Pt–Pd catalysts showed better CO tolerance and higher TON than PtRu/C catalyst.•Pt0.59Pd0.324Cu0.167/C catalyst exhibited the best mass activity toward MOR and EOR.
Abstract
Brain markers of oxidative damage increase with advancing age. In response, brain antioxidant levels may also increase with age, although this has not been well investigated. Here, we used ...edited magnetic resonance spectroscopy to quantify endogenous levels of glutathione (GSH, one of the most abundant brain antioxidants) in 37 young mean: 21.8 (2.5) years; 19 female and 23 older adults mean: 72.8 (8.9) years; 19 female. Accounting for age-related atrophy, we identified higher frontal and sensorimotor GSH levels for the older compared with the younger adults. For the older adults only, higher sensorimotor (but not frontal) GSH was correlated with poorer balance and gait. This suggests a regionally specific relationship between higher brain oxidative stress levels and motor performance declines with age. We suggest these findings reflect an upregulation of GSH in response to increasing brain oxidative stress with normal aging. Together, these results provide insight into age differences in brain antioxidant levels and implications for motor function.
The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain ...molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies.
We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data.
Whole-exome sequencing resulted in 95%–99% of the target regions covered at a mean depth of 133–490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens.
We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.
Aims. We study the Galactic large-scale synchrotron emission by generating a reliable all-sky spectral index map and temperature map at 45 MHz. Methods. We use our observations, the published all-sky ...map at 408 MHz, and a bibliographical compilation to produce a map corrected for zero-level offset and extragalactic contribution. Results. We present full sky maps of the Galactic emission at 45 MHz and the Galactic spectral index between 45 and 408 MHz with an angular resolution of 5°. The spectral index varies between 2.1 and 2.7, reaching values below 2.5 at low latitude because of thermal free-free absorption and its maximum in the zone next to the Northern Spur.
Dietary fiber and phenolic compounds are two recognized dietary factors responsible for potential effects on human health; therefore, they have been widely used to increase functionality of some ...foods. This paper focuses on showing the use of both substances as functional ingredients for enriching foods, and at the same time, describes the use of a single material that combines the properties of the two types of substances. The last part of the work describes some facts related to the interaction between dietary fiber and phenolic compounds, which could affect the bioaccessibility and absorption of phenolics in the gut. In this sense, the purpose of the present review is to compile and analyze evidence relating to the use of dietary fiber and phenolic compounds to enhance technological and nutritional properties of foods and hypothesize some of the possible effects in the gut after their ingestion.
Dietary fiber and phenolic compounds are responsible for potential effects on human health; therefore they have been widely used to increase functionality of some foods.
Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor‐induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, ...facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen‐specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor‐induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor‐released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential.
In this study, we use our recently developed 3D DC‐tumor co‐culture system to investigate how patient‐derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen‐based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor‐corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T‐cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14+ CD1c+ CD163+) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti‐IL‐6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL‐6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor‐induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches.
This research investigates CRC impact on cDC2 in a 3D collagen model with patient‐derived organoids. Tumor‐exposed cDC2 shift toward a CD14+ phenotype resembling DC3, linked to impaired T‐cell activation. This is partially mediated by PGE2 and IL‐6, offering insights into CRC‐induced cDC2 dysfunction with potential implications for therapeutic design.
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•Multiple nanoemulsion encapsulates complex natural extracts with high efficiency.•The prototype freeze-dried, maintaining the stability of encapsulated compounds.•The antioxidant ...effect of polyphenols improves when they are nanoencapsulated.•The multiple nanoemulsion shows a high antibacterial effect against S.pyogenes.•The Innovative nanoemulsion allows intestinal absorption of polyphenols.
Beehive derivatives, including honeybee pollen (HBP), have been extensively studied for their beneficial health properties and potential therapeutic use. Its high polyphenol content gives it excellent antioxidant and antibacterial properties. Today its use is limited due to poor organoleptic properties, low solubility, stability, and permeability under physiological conditions. A novel edible multiple W/O/W nanoemulsion (BP-MNE) to encapsulate the HBP extract was designed and optimized to overcome these limitations. The new BP-MNE has a small size (∼100 nm), a zeta potential greater than +30 mV, and efficiently encapsulated phenolic compounds (∼82%). BP-MNE stability was measured under simulated physiological conditions and storage conditions (4 months); in both cases, stability was promoted. The formulation's antioxidant and antibacterial (Streptococcus pyogenes) activity was analyzed, obtaining a higher effect than the non-encapsulated compounds in both cases. In vitro permeability was tested, observing a high permeability of the phenolic compounds when they are nanoencapsulated. With these results, we propose our BP-MNE as an innovative solution to encapsulate complex matrices, such as HBP extract, as a platform to develop functional foods.
The goal of this practice statement is to help members and their multidisciplinary teams recognize infusion reactions and hypersensitivity reactions in the clinical setting. It will provide ...recommendations to help guide response to reactions and desensitization when appropriate, to promote safe use of chemotherapeutic agents among all providers in the delivery process.
A multi-disciplinary team of healthcare professionals from the Society of Gynecologic Oncology Education Committee collaborated to review peer reviewed literature and guidelines to develop a practice statement on the management of chemotherapy hypersensitivity reactions and desensitization regimens.
There is always potential for a patient to have a reaction to any medication, with both infusion reactions and hypersensitivity reactions potentially occurring in the treatment of gynecologic cancers. Premedication to prevent reactions should be given at least prior to infusion for regimens that include the most common agents associated with reactions. At the time when reaction is occurring it might be difficult to distinguish between an infusion reaction versus true hypersensitivity given the similarities in signs and symptoms, therefore it is important that orders to manage reactions be included in every chemotherapy order set so the infusion nurse can provide immediate interventions while waiting for the provider to arrive to assess the patient. Desensitization is a potential option to allow the patient to continue to receive the offending agent. While a variety of desensitization regimens have been presented in the literature, the goal is to minimize steps and variability to decrease opportunity for errors during chemotherapy preparation or administration.
Incorporating a review of the literature and clinical experience from the SGO Education Committee, this paper provides an overview of current approaches for prevention and management of reactions to commonly used chemotherapy agents for gynecologic cancers.
•Hypersensitivity and infusion reactions to antineoplastic therapies challenge the treatment of cancer patients.•Reactions require a multi-disciplinary team to decide on a protocol best suited to their patients within their institution.•Every effort should be made to streamline the process and protocols to reduce error during mixing and administration.•An overview is provided of approaches for prevention and management of reactions to agents used for gynecologic cancers.
Extracellular vesicles (EVs) have become important in embryo-maternal communication during early development. The aim of this study was to evaluate the effect of an in vitro system on early ...bidirectional embryo-maternal communication mediated by EVs. For this purpose, two experiments were performed: one to evaluate the effect of embryonic EVs on maternal cells and the second to determine the effect of maternal EVs on early embryonic development. For the first in vitro (IVP) and in vivo (IVV) experiments, bovine blastocysts were selected and individually cultured for 48 h to collect embryonic EVs secreted during days 7-9 of embryonic development. Embryonic EVs were added to the medium of in vitro-cultured bovine endometrial cells to evaluate their effect on the expression pattern of genes associated with endometrial function and response to interferon tau (IFNT). Non-classical interferon-stimulated genes (ISGs) were only induced by in vitro-derived embryos. In the second experiment, EVs released by endometrial cells cultured in vitro (EVC) and collected from uterine fluid (EV-UF) of cows in the early luteal phase were added to the culture medium of bovine embryos produced in vitro during days 5-9 of development. The effect of maternal in vitro or in vivo-derived EVs differs in the quality of bovine embryos produced in vitro during the pre-implantation period. The expression of IFNT in bovine embryos is increased by the effect of EV-UF treatment. Additionally, EV-UF treatment induces a sustained increase in diameter during embryonic development and a tendency towards a greater number of expanded and hatched blastocysts. However, some genes related to embryo quality are induced by EVC treatment.
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