MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma, namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies, may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.

SARS-CoV-2-positive patients display considerable differences in proteome diversity in urine, nasopharyngeal, gargle solution and bronchoalveolar lavage fluid samples

Background: Proteome profile changes post-severe acute respiratory syndrome coronavirus 2 (post-SARS-CoV-2) infection in different body sites of humans remains an active scientific investigation whose solutions stand a chance of providing more information on what constitutes SARS-CoV-2 pathogenesis. While proteomics has been used to understand SARS-CoV-2 pathogenesis, there are limited data about the status of proteome profile in different human body sites infected by sarscov2 virus. To bridge this gap, our study aims to profile the proteins secreted in urine, bronchoalveolar lavage fluid (BALF), gargle solution, and nasopharyngeal samples and assess the proteome differences in these body samples collected from SARS-CoV-2-positive patients. Materials and methods: We downloaded publicly available proteomic data from (https://www.ebi.ac.uk/pride/). The data we downloaded had the following identifiers: i) PXD019423, n=3 from Charles Tanford Protein Center in Germany. ii) PXD018970, n=15 from Beijing Proteome Research Centre, China. iii)PXD022085, n=5 from Huazhong University of Science and Technology, China, and iv) PXD022889, n=18 from Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA. MaxQuant was used for the peptide spectral matching using human and SARS-CoV-2 downloaded from UniProt database (access date 13th October 2021). Results: The individuals infected with SARS-CoV-2 viruses displayed a different proteome diversity from the different body sites we investigated. Overally, we identified 1809 proteins across the four different sample types we compared. Urine and BALF samples had significantly more abundant SARS-CoV-2 proteins than the other body sites we compared. Urine samples had 257(33.7%) unique proteins followed by nasopharyngeal with 250(32.8%) unique proteins. Garlge solution and BALF had 38(5%) and 73(9.6%) unique proteins respectively. Conclusions: Urine, gargle solution, nasopharyngeal, and bronchoalveolar lavage fluid samples have different protein diversity in individuals infected with SARS-CoV-2. Moreover, our data also demonstrated that a given body site is characterized by a unique set of proteins in SARS-CoV-2 seropositive individuals. Key words: SARS-CoV-2, body sites,urine,gargle solution, BALF,nasopharyngeal

Estimation of CFETR performance and burning fraction in different pellet fueling scenarios by a multi-species radial transport model

Tritium self-sufficiency in future DT fusion reactor is a crucial challenge. As an engineering test reactor, CFETR requires a burning fraction of 3% for the goal to test the accessibility to the future fusion plant. To self-consistently simulate burning plasmas with profile changes in pellet injection scenarios and to estimate the corresponding burning fraction, a one-dimensional (1-D) multi-species radial transport model is developed in BOUT++ frame. Several pellet-fueling scenarios are then tested in the model. Results show that the increased fueling depth improves the burning fraction by particle confinement improvement and fusion power increase. Nevertheless, by increasing the depth, the pellet cooling-down may significantly lower the temperature in the core region. Taking the density perturbation into consideration, the reasonable parameters of the fueling scenario in these simulations are estimated as the pellet radius r_p=3 mm, the injection rate = 4 Hz , the pellet injection velocity =1000–2000 m/s without drift or 450 m/s with high filed side (HFS) drift.

CFD Evaluation of Heat Transfer and NOx Emissions When Converting a Tangentially Fired Coal Boiler to Use Methane

The need to reduce global carbon dioxide (CO2) emissions is driving the conversion of coal-fired power plants to use methane, which can reduce CO2 emissions by >40%. However, conducting gas firing in coal boilers changes the heat transfer profile; therefore, preliminary evaluations using computational fluid dynamics are required prior to conversion. Here, methane was used as a heat input source in the simulation of an existing coal boiler, and combustion, nitrogen oxides (NOx) emission characteristics, and heat transfer profile changes inside the boiler were analyzed. Furthermore, changes in the burner zone stoichiometric ratio (BZSR) were simulated to restore the decreased heat absorption of the furnace waterwall, revealing that air distribution could change the heat absorption of the waterwall and tube bundles. However, this change was smaller than that caused by conversion from coal to methane. Therefore, to implement gas firing in coal boilers, alternatives such as output derating, using an attemperator, or modifying heat transfer surfaces are necessary. Despite these limitations, a 70% reduction in NOx emissions was achieved at a BZSR of 0.76, compared with coal. As the BZSR contributes significantly to NOx emissions, conducting gas firing in existing coal boilers could significantly reduce NOx and CO2 emissions.

A Brief Analysis of Proteomic Profile Changes during Zebrafish Regeneration

Unlike mammals, zebrafish are capable to regenerate many of their organs, however, the response of tissue damage varies across tissues. Understanding the molecular mechanism behind the robust regenerative capacity in a model organism may help to identify and develop novel treatment strategies for mammals (including humans). Hence, we systematically analyzed the current literature on the proteome profile collected from different regenerated zebrafish tissues. Our analyses underlining that several proteins and protein families responsible as a component of cytoskeleton and structure, protein synthesis and degradation, cell cycle control, and energy metabolism were frequently identified. Moreover, target proteins responsible for the initiation of the regeneration process, such as inflammation and immune response were less frequently detected. This highlights the limitation of previous proteomic analysis and suggested a more sensitive modern proteomics analysis is needed to unfold the mechanism. This brief report provides a list of target proteins with predicted functions that could be useful for further biological studies.

Relationship of smoking with COVID-19 and its adverse effects

There is a direct relationship between COVID-19 and smoking. This relationship has detrimental consequences for smoking and COVID-19 on body physiology. Smoking causes disc herniation, lungs diseases, heart illness, lipid profile changes, muscle protein synthesis declines, head, neck, and gastric cancers, cerebral inflammation, weight loss and obesity. The smoking habit of pregnant women leads to miscarriage, poor foetal growth, and low lipid and protein levels in breast milk. In males, it also reduces semen ejaculation and seminal vesicle volume. The treatment is based on quitting the smoking. Preventive measures such as a healthy diet and regular exercise can help to mitigate the negative consequences of smoking. In addition, smoking has been recognised as a major factor in COVID-19 transmission. Tobacco smokers are at increased risk of serious COVID-19 infection due to poor lung function, cross-infection, and vulnerable hygiene behaviors. People who have smoked in the past are thought to be more susceptible than non-smokers to have more severe COVID-19 illness symptoms. COVID-19 is more common among smokers than nonsmokers. Current smokers are five times more likely to have influenza infection than non-smokers. Smoking has been identified as one of the risk factors linked to infection and death.

Age-Related Progression of Microvascular Dysfunction in Cystic Fibrosis: New Detection Ways and Clinical Outcomes

There are concerns about altered vascular functions that could play an important role in the pathogenesis and influence the severity of chronic disease, however, increased cardiovascular risk in paediatric cystic fibrosis (CF) has not been yet fully understood. Aim was to analyse vascular disease risk and investigate changes over times in CF and controls. We prospectively enrolled 22 CF subjects (a median age of 16.07 years), and 22 healthy demographically matched controls (a median age of 17.28 years) and determined endothelial function. We utilised a combined diagnostic approach by measuring the plethysmographic Reactive Hyperemia Index (RHI) as the post-to preocclusive endothelium-dependent changes of vascular tone, and biomarkers that are known to be related to endothelial dysfunction (ED): asymmetric dimethyl arginine (ADMA), high-sensitive CRP (hsCRP), VCAM-1 and E-selectin. RHI values were significantly lower in CF young adults (p<0.005). HsCRP (p<0.005), E-selectin (p<0.001) and VCAM-1 (p<0.001) were significantly increased in CF patients since childhood. The findings have provided a detailed account of the ongoing process of microvascular dysfunction with gradual progression with the age of CF patients, making them further at risk of advanced vascular disease. Elevations of biomarkers in CF children with not yet demonstrated RHI changes but with significantly reduced RHI in adulthood and lipid profile changes indicate the possible occurrence of ED with CF-related specific risk factors over time and will enable us to provide the best possible support.

Age-Related Changes of Gene Expression Profiles in Drosophila

An individual’s gene expression profile changes throughout their life. This change in gene expression is shaped by differences in physiological needs and functions between the younger and older organism. Despite intensive studies, the aging process is not fully understood, and several genes involved in this process may remain to be identified. Here we report a transcriptomic analysis of Drosophila melanogaster using microarrays. We compared the expression profiles of two-day-old female adult flies with those of 45-day-old flies. We identified 1184 genes with pronounced differences in expression level between young and old age groups. Most genes involved in muscle development/maintenance that display different levels of expression with age were downregulated in older flies. Many of these genes contributed to sarcomere formation and function. Several of these genes were functionally related to direct and indirect flight muscles; some of them were exclusively expressed in these muscles. Conversely, several genes involved in apoptosis processes were upregulated in aging flies. In addition, several genes involved in resistance to toxic chemicals were upregulated in aging flies, which is consistent with a global upregulation of the defense response system in aging flies. Finally, we randomly selected 12 genes among 232 genes with unknown function and generated transgenic flies expressing recombinant proteins fused with GFP protein to determine their subcellular expression. We also found that the knockdown of some of those 12 genes can affect the lifespan of flies.