Tumour angiogenesis normalized by myo-inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response.

Pathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo-inositol-trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO ) and stabilizes vessel normalization through activation of endothelial Phosphatase-and-Tensin-homologue (PTEN).

Peptide nucleic acid Hoogsteen strand linker design for major groove recognition of DNA thymine bases.

Sequence-specific targeting of double-stranded DNA and non-coding RNA via triple-helix-forming peptide nucleic acids (PNAs) has attracted considerable attention in therapeutic, diagnostic and nanotechnological fields. An E-base (3-oxo-2,3-dihydropyridazine), attached to the polyamide backbone of a PNA Hoogsteen strand by a side-chain linker molecule, is typically used in the hydrogen bond recognition of the 4-oxo group of thymine and uracil nucleic acid bases in the major groove. We report on the application of quantum chemical computational methods, in conjunction with spatial constraints derived from the experimental structure of a homopyrimidine PNA·DNA-PNA hetero-triplex, to investigate the influence of linker flexibility on binding interactions of the E-base with thymine and uracil bases in geometry-optimised model systems.

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations.

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD (HREMD) led to unbiased and accurate ensembles, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of varying sequence properties using two recently optimized force fields, indicating the general applicability of HREMD for IDPs.

Construction of Highly Ordered Glyco-Inside Nano-Assemblies through RAFT Dispersion Polymerization of Galactose-Decorated Monomer.

Glyco-assemblies derived from amphiphilic sugar-decorated block copolymers (ASBCs) have emerged prominently due to their wide application, for example, in biomedicine and as drug carriers. However, to efficiently construct these glyco-assemblies is still a challenge. Herein, we report an efficient technology for the synthesis of glyco-inside nano-assemblies by utilizing RAFT polymerization of a galactose-decorated methacrylate for polymerization-induced self-assembly (PISA).

Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies.

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties.

GTP-dependent formation of straight tubulin oligomers leads to microtubule nucleation.

Nucleation of microtubules (MTs) is essential for cellular activities, but its mechanism is unknown because of the difficulty involved in capturing rare stochastic events in the early stage of polymerization. Here, combining rapid flush negative stain electron microscopy (EM) and kinetic analysis, we demonstrate that the formation of straight oligomers of critical size is essential for nucleation. Both GDP and GTP tubulin form single-stranded oligomers with a broad range of curvatures, but upon nucleation, the curvature distribution of GTP oligomers is shifted to produce a minor population of straight oligomers.

Endothelial Cells as Tools to Model Tissue Microenvironment in Hypoxia-Dependent Pathologies.

Endothelial cells (ECs) lining the blood vessels are important players in many biological phenomena but are crucial in hypoxia-dependent diseases where their deregulation contributes to pathology. On the other hand, processes mediated by ECs, such as angiogenesis, vessel permeability, interactions with cells and factors circulating in the blood, maintain homeostasis of the organism. Understanding the diversity and heterogeneity of ECs in different tissues and during various biological processes is crucial in biomedical research to properly develop our knowledge on many diseases, including cancer.

Deleterious Effects of an Air Pollutant (NO) on a Selection of Commensal Skin Bacterial Strains, Potential Contributor to Dysbiosis?

The skin constitutes with its microbiota the first line of body defense against exogenous stress including air pollution. Especially in urban or sub-urban areas, it is continuously exposed to many environmental pollutants including gaseous nitrogen dioxide (gNO). Nowadays, it is well established that air pollution has major effects on the human skin, inducing various diseases often associated with microbial dysbiosis.

The carboxylation status of osteocalcin has important consequences for its structure and dynamics.

Background: The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated.

Methods: Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2.

Emerging advances in synthetic cancer nano-vaccines: opportunities and challenges.

: Cancer immunotherapy is a fast-growing field that has achieved tremendous progress in recent years. It is one of the most potent tools that can activate the immune system against cancer. Nevertheless, the development of safe and effective vaccines to overcome emerging new disease remains challenging since several emerging antigens are poorly immunogenic.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (M) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M, a cysteine protease, have been determined, facilitating structure-based drug design. M plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day.

Tuning Proton Transfer Thermodynamics in SARS-Cov-2 Main Protease: Implications for Catalysis and Inhibitor Design.

In this comutational work a hybrid quantum mechanics/molecular mechanics approach, the MD-PMM approach, is used to investigate the proton transfer reaction the activates the catalytic activity of SARS-CoV-2 main protease. The proton transfer thermodynamics is investigated for the apo ensyme (i.e.

Effects of sodium and calcium chloride ionic stresses on model yeast membranes revealed by molecular dynamics simulation.

As efforts to move a renewable economy grow, it will be necessary to make use of microbial conversion strategies for the production of novel materials or the upgrading of waste to high-value products. One critical technical challenge currently limiting waste upgrading remains the difficulty in obtaining single-pot conversion techniques where physical, chemical, and biological conversion are performed in a single step. To overcome this challenge, a detailed understanding of how different stresses impact microbial membrane stability will be necessary.

Children were less frequently infected with SARS-CoV-2 than adults during 2020 COVID-19 pandemic in Warsaw, Poland.

Clinical data suggest that during the current COVID-19 pandemic, children are less prone than adults to SARS-CoV-2 infection. Our purpose was to determine the frequency of SARS-CoV-2 in children vs. adults during the 2020 pandemic in Warsaw, Poland, and to investigate whether RSV and/or influenza A/B infections were associated with SARS-CoV-2 infections.

Molecular Dynamics Simulation of the Structures, Dynamics, and Aggregation of Dissolved Organic Matter.

Dissolved organic matter (DOM) plays a significant role in the transport and transformation of pollutants in the aquatic environment. However, the experimental characterization of DOM has been limited mainly to bulk properties, and the molecular-level interactions among various components of DOM remain to be fully characterized. Here, we use molecular dynamics (MD) simulations to probe the structural properties of model DOM systems at atomic detail.

Insight into the Catalytic Mechanism of GH11 Xylanase: Computational Analysis of Substrate Distortion Based on a Neutron Structure.

The reaction mechanism of biomass decomposition by xylanases remains the subject of debate. To clarify the mechanism we investigated the glycosylation step of GH11 xylanase, an enzyme that catalyzes the hydrolysis of lignocellulosic hemicellulose (xylan). Making use of a recent neutron crystal structure, which revealed the protonation states of relevant residues, we used ab initio quantum mechanics/molecular mechanics (QM/MM) calculations to determine the detailed reaction mechanism of the glycosylation step.

Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.

Background: Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms.

Methods: We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mice.

Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa.

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialylated glycans displayed on human platelets.

Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-receptor.

Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively.

Metabolomic Nuclear Magnetic Resonance Studies at Presymptomatic and Symptomatic Stages of Huntington's Disease on a Model.

Huntington's disease (HD) is an inherited neurodegenerative disorder, for which diagnostic development and discovery of new therapeutic targets are urgently required. In this study, a model of HD in has been used to identify metabolic biomarkers at presymptomatic and symptomatic stages of the disease. The pan-neuronal expression of a pathogenic fragment of the human Huntingtin (HTT) protein containing a 93-repeat polyglutamine expansion (Httex1p Q93) in transgenic flies induces a neuropathology with several characteristics of the human disease.

Combining Three-Dimensional Modeling with Artificial Intelligence to Increase Specificity and Precision in Peptide-MHC Binding Predictions.

The reliable prediction of the affinity of candidate peptides for the MHC is important for predicting their potential antigenicity and thus influences medical applications, such as decisions on their inclusion in T cell-based vaccines. In this study, we present a rapid, predictive computational approach that combines a popular, sequence-based artificial neural network method, NetMHCpan 4.0, with three-dimensional structural modeling.

Bovine Organospecific Microvascular Endothelial Cell Lines as New and Relevant In Vitro Models to Study Viral Infections.

Microvascular endothelial cells constitute potential targets for exogenous microorganisms, in particular for vector-borne pathogens. Their phenotypic and functional variations according to the organs they are coming from provide an explanation of the organ selectivity expressed in vivo by pathogens. In order to make available relevant tools for in vitro studies of infection mechanisms, our aim was to immortalize bovine organospecific endothelial cells but also to assess their permissivity to viral infection.

Deconstruction of biomass enabled by local demixing of cosolvents at cellulose and lignin surfaces.

A particularly promising approach to deconstructing and fractionating lignocellulosic biomass to produce green renewable fuels and high-value chemicals pretreats the biomass with organic solvents in aqueous solution. Here, neutron scattering and molecular-dynamics simulations reveal the temperature-dependent morphological changes in poplar wood biomass during tetrahydrofuran (THF):water pretreatment and provide a mechanism by which the solvent components drive efficient biomass breakdown. Whereas lignin dissociates over a wide temperature range (>25 °C) cellulose disruption occurs only above 150 °C.