Commonly used commercial cast aluminum alloys for the automotive industry are viable for temperatures only up to 250 °C, despite decades of study and development. Affordable cast aluminum alloys with ...improved high-temperature mechanical properties are needed to enable the next generation of higher efficiency passenger car engines. Metastable θ′ (Al2Cu) precipitates contribute to strengthening in Al–Cu alloys, but above 250 °C coarsen and transform, leading to poor mechanical properties. A major challenge has been to inhibit coarsening and transformation by stabilizing the metastable precipitates to higher temperatures. Here, we report compositions and associated counter-intuitive microstructures that allow cast Al–Cu alloys to retain their strength after lengthy exposures up to 350 °C, ∼70% of their absolute melting point. Atomic-scale characterization along with first-principles calculations demonstrate that microalloying with Mn and Zr (while simultaneously limiting Si to < 0.1 wt %) is key to stabilization of high-energy interfaces. It is suggested that segregation of Mn and Zr to the θ′ precipitate-matrix interfaces provides the mechanism by which the precipitates are stabilized to a higher homologous temperature.
Therapeutic Immunization against Glioblastoma Schijns, Virgil E J C; Pretto, Chrystel; Strik, Anna M ...
International journal of molecular sciences,
08/2018, Letnik:
19, Številka:
9
Journal Article
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Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually ...surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient's immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.
Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One ...locus for autosomal dominant CCM (CCM1) maps to chromosome 7q21–q22. Recombination events in linked family members define a critical region of ∼2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angio-genesis and cerebrovascular disease.
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people ...worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
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•Phosphoproteomics analysis of SARS-CoV-2-infected cells uncovers signaling rewiring•Infection promotes host p38 MAPK cascade activity and shutdown of mitotic kinases•Infection stimulates CK2-containing filopodial protrusions with budding virus•Kinase activity analysis identifies potent antiviral drugs and compounds
Phosphoproteomics analysis of SARS-CoV-2-infected Vero E6 cells reveals host cellular pathways hijacked by viral infection, leading to the identification of small molecules that target dysregulated pathways and elicit potent antiviral efficacy.
Mass spectrometry (MS) based quantitative approaches typically require a thorough sample clean-up and a decent chromatographic step in order to achieve needed figures of merit. However, in most ...cases, such processes are not optimal for urgent assessments and high-throughput determinations. The direct coupling of solid phase microextraction (SPME) to MS has shown great potential to shorten the total sample analysis time of complex matrices, as well as to diminish potential matrix effects and instrument contamination. In this study, we demonstrate the use of the open-port probe (OPP) as a direct and robust sampling interface to couple biocompatible-SPME (Bio-SPME) fibres to MS for the rapid quantitation of opioid isomers (i.e. codeine and hydrocodone) in human plasma. In place of chromatography, a differential mobility spectrometry (DMS) device was implemented to provide the essential selectivity required to quantify these constitutional isomers. Taking advantage of the simplified sample preparation process based on Bio-SPME and the fast separation with DMS-MS coupling via OPP, a high-throughput assay (10–15 s per sample) with limits of detection in the sub-ng/mL range was developed. Succinctly, we demonstrated that by tuning adequate ion mobility separation conditions, SPME-OPP-MS can be employed to quantify non-resolved compounds or those otherwise hindered by co-extracted isobaric interferences without further need of coupling to other separation platforms.
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•Differential mobility spectrometry (DMS) provide the selectivity required to quantify opioid isomers.•Matrix compatible Solid Phase Microextraction (SPME) facilitated clean rapid extraction from plasma.•Open-port probe provide convenient interface for introduction of SPME device to mass spectrometer.
Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic ...alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.
We retrospectively reviewed 2989 consecutive patients with a mean age of 81 (21 to 105) and a female to male ratio of 5:2 who were admitted to our hip fracture unit between July 2009 and February ...2013. We compared weekday and weekend admission and weekday and weekend surgery 30-day mortality rates for hip fractures treated both surgically and conservatively. After adjusting for confounders, weekend admission was independently and significantly associated with a rise in 30-day mortality (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.02 to 1.9; p = 0.039) for patients undergoing hip fracture surgery. There was no increase in mortality associated with weekend surgery (OR 1.2, 95% CI 0.8 to 1.7; p = 0.39). All hip fracture patients, whether managed surgically or conservatively, were more likely to die as an inpatient when admitted at the weekend (OR 1.4, 95% CI 1.02 to 1.80; p = 0.032), despite our unit having a comparatively low overall inpatient mortality (8.7%). Hip fracture patients admitted over the weekend appear to have a greater risk of death despite having a consultant-led service.
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