Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent antigen cross-reactivity of the T cell receptor (TCR) is balanced by high specificity. Surprisingly, TCR specificity often manifests in ways not easily interpreted from static structures. Here we show that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen and its wild-type (WT) counterpart emerges from distinct motions within the HLA-A3 peptide binding groove that vary with the identity of the peptide's first primary anchor.

The Evolving T Cell Receptor Recognition Code: The Rules Are More Like Guidelines.

αβ T cell receptor (TCR) recognition of peptide-MHC complexes lies at the core of adaptive immunity, balancing specificity and cross-reactivity to facilitate effective antigen discrimination. Early structural studies established basic frameworks helpful for understanding and contextualizing TCR recognition and features such as peptide specificity and MHC restriction. However, the growing TCR structural database and studies launched from structural work continue to reveal exceptions to common assumptions and simplifications derived from earlier work.

Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells.

Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor.

Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional, but how this dysfunction affects cancer progression in humans is unknown. We infused C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming.

SARS-CoV-2 spike does not interact with the T cell receptor or directly activate T cells.

SARS-CoV-2infection can induce multisystem inflammatory syndrome in children, which resembles superantigen-induced toxic shock syndrome. Recent work has suggested that the SARS-CoV-2 spike (S) protein could act as a superantigen by binding T cell receptors (TCRs) and inducing broad antigen-independent T cell responses. Structure-based computational modeling identified potential TCR-binding sites near the S receptor-binding domain, in addition to a site with homology to known neurotoxins.

Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide's first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding.

Blockade of sympathetic ganglia improves vascular dysfunction in septic shock.

Sepsis/septic shock activates the sympathetic nervous system (SNS) to deal with the infection stress. However, an imbalanced or maladaptive response due to excessive or uncontrolled activation characterizes autonomic dysfunction. Our hypothesis was that reducing this excessive activation of the autonomic nervous system would impact positively in sepsis.

Structural and physical features that distinguish tumor-controlling from inactive cancer neoepitopes.

Neoepitopes arising from amino acid substitutions due to single nucleotide polymorphisms are targets of T cell immune responses to cancer and are of significant interest in the development of cancer vaccines. However, understanding the characteristics of rare protective neoepitopes that truly control tumor growth has been a challenge, due to their scarcity as well as the challenge of verifying true, neoepitope-dependent tumor control in humans. Taking advantage of recent work in mouse models that circumvented these challenges, here, we compared the structural and physical properties of neoepitopes that range from fully protective to immunologically inactive.

CD8+ T Cell-Dependent Antitumor Activity In Vivo of a Mass Spectrometry-Identified Neoepitope despite Undetectable CD8+ Immunogenicity In Vitro.

Identification of neoepitopes that can control tumor growth in vivo remains a challenge even 10 y after the first genomics-defined cancer neoepitopes were identified. In this study, we identify a neoepitope, resulting from a mutation in the junction plakoglobin (Jup) gene (chromosome 11), from the mouse colon cancer line MC38-FABF (C57BL/6). This neoepitope, Jup mutant (JupMUT), was detected during mass spectrometry of MHC class I-eluted peptides from the tumor.

Cannabinoid CB receptor agonist reduces local and systemic inflammation associated with pneumonia-induced sepsis in mice.

Sepsis is a severe condition secondary to dysregulated host response to infection leading to tissue damage and organ dysfunction. Cannabinoid CB receptor has modulatory effects on the immune response. Therefore, this study investigated the effects of a cannabinoid CB receptor agonist on the local and systemic inflammatory process associated with pneumonia-induced sepsis.

Plant-derived polyphenolic compounds: nanodelivery through polysaccharide-based systems to improve the biological properties.

Plant-derived polyphenols are naturally occurring compounds widely distributed in plants. They have received greater attention in the food and pharmaceutical industries due to their potential health benefits, reducing the risk of some chronic diseases due to their antioxidant, anti-inflammatory, anticancer, cardioprotective, and neuro-action properties. Polyphenolic compounds orally administered can be used as adjuvants in several treatments but with restricted uses due to chemical instability.

Valorization of polyphenolic compounds from food industry by-products for application in polysaccharide-based nanoparticles.

In the last decades, evidence has indicated the beneficial properties of dietary polyphenols. and studies support that the regular intake of these compounds may be a strategy to reduce the risks of some chronic non-communicable diseases. Despite their beneficial properties, they are poorly bioavailable compounds.

Mitochondrial metabolism in primary and metastatic human kidney cancers.

Most kidney cancers display evidence of metabolic dysfunction but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours.

Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.

Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: and .

Pectin-based nanoencapsulation strategy to improve the bioavailability of bioactive compounds.

Pectin is one of the polysaccharides to be used as a coating nanomaterial. The characteristics of pectin are suitable to form nanostructures for protection, increased absorption, and bioavailability of different active compounds. This review aims to point out the structural features of pectins and their use as nanocarriers.

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from -mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism.

Nanoencapsulated anthocyanin as a functional ingredient: Technological application and future perspectives.

Anthocyanins are an important group of phenolic compounds responsible for pigmentation in several plants, and regular consumption is associated with a reduced risk of several diseases. However, the application of anthocyanins in foods represents a challenge due to molecular instability. The encapsulation of anthocyanins in nanostructures is a viable way to protect from the factors responsible for degradation and enable the industrial application of these compounds.

Nanotechnology as a Tool to Mitigate the Effects of Intestinal Microbiota on Metabolization of Anthocyanins.

Anthocyanins are an important group of phenolic compounds responsible for pigmentation in several plants. For humans, a regular intake is associated with a reduced risk of several diseases. However, molecular instability reduces the absorption and bioavailability of these compounds.

Dynamics of GRK2 in the kidney: a putative mechanism for sepsis-associated kidney injury.

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP).

Incidence and Mortality Trends of Acute Gastroenteritis and Pneumococcal Disease in Children Following Universal Rotavirus and Pneumococcal Conjugate Vaccination in Ecuador.

Introduction: Ecuador introduced routine infant rotavirus (RV) vaccination in 2008 and pneumococcal conjugate vaccination (PCV) in 2011 to manage disease and mortality in children caused by gastroenteritis (GE) and by pneumonia (PNE) and invasive pneumococcal disease (IPD), respectively.

Methods: This retrospective ecological database study described vaccination coverage as well as the trends in incidence and mortality in the pre- versus post-vaccination periods and used time-trend analysis models to assess the impact of vaccination.

Results: RV vaccination coverage of the second dose was between 79-97% from 2008 to 2016.

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing - Review.

Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations.