The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxia induced apoptosis occurs. These resistant tumours probably have a more aggressive phenotype and may have decreased responsiveness to treatment. The key regulator of this process, hypoxia inducible factor 1 (HIF-1), can initiate apoptosis by inducing high concentrations of proapoptotic proteins, such as BNIP3, and can cause stabilisation of p53. However, during hypoxia, antiapoptotic proteins, such as IAP-2, can be induced, whereas the proapoptotic protein Bax can be downregulated. During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. Understanding the regulation of apoptosis during hypoxia and the mechanisms of resistance to apoptosis might lead to more specific treatments for solid tumours

Polyoxometallate ions as models for mineral nanoparticle interactions with proteins

Mineral nanoparticles (NPs) form naturally by weathering of rock, and artificially by industry. They are abundant in our surroundings, so it is important to know what the effects on living organisms might be. NPs often interact with proteins, important building blocks and biocatalysts in all living things. The potential effects of NPs on proteins could be either detrimental or beneficial, and it is important to know which. Using a model system, we have identified a number of factors which can affect how NPs interact with biomolecules. These are: 1) the polarity of the metal-oxide bond, as determined by the metal atom’s electronegativity; 2) the hydrophobicity of the ligand, determined in our model by the length of an oligoglycine; 3) the ionic strength of the solution, as cations in excess will compete for binding spots with the ligand, replacing it on the NP surface; 4) The shape of the ligand, as demonstrated by structure determining peptides; 5) The relative affinity of ligands, as shown by one NP readily crystallizing with a buffer molecule rather than a peptide, but not interacting noticeably with a similar buffer. Certain NPs are unstable under specific conditions, such as pH, while others tolerate it, and complexes with ligands can differ for these NPs. In addition, compounds used in the model were used as a model in a study on antiviral activity, and were also used to produce a Sol-Gel material with remarkable efficacy in electrocatalytic water splitting

Variable EBV DNA load distributions and heterogeneous EBV mRNA expression patterns in the circulation of solid organ versus stem cell transplant recipients

Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially life-threatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell-associated EBV DNA showed BARTs an

Unveiling POM-peptide complexes: molecular insights into metal oxide nanoparticle-protein interactions

Mineral nanoparticles (NPs) play a crucial role in biological systems, exhibiting enzyme-like "nanozyme" activity in protein oxidation and hydrolysis. To study NP interactions at the molecular level, we characterized complexes of peptides with poly-oxo-metalate (POM) species, the smallest known NPs. Our findings highlight the importance of factors such as metal-oxygen bond polarity, peptide hydrophilicity, medium conditions, and structure-directing amino acids. Using single-crystal models and 2D NMR, we also explored interactions between larger NPs as nanozymes and proteins relevant for specific oxidation of amino acids and proteins

The trees in urban cities : A study of four municipal tree policies

Allt eftersom städer växer blir de urbana miljöerna mer hårdgjorda. De hårdgjorda ytorna skapar ett varmare lokalklimat och skapar en ökad ytavrinning. Det tuffa förhållandet i städerna med hårdgjorda ytor kan göra det svårt för stadsträd att bli gamla och vidare exploatering i städer riskerar att skada träden. För att skapa ett hållbart trädbestånd med vitala träd som kan bidra till att minska den lokala temperaturökningen och ta hand om dagvatten krävs styrdokument som prioriterar träden. Inom kommuner arbetar man med olika styrdokument som ska bidra till att värna om stadsträden, ett av de övergripande styrdokumenten är en trädpolicy. Arbetets syfte är att undersöka om olika kommuners trädpolicyer är likvärdiga och om de är aktuella samt användbara dokument. För att svara på syftet genomfördes en dokumentanalys och en intervjustudie. Dokumentanalysen berör fyra svenska kommuner och i intervjustudien tre personer som arbetar inom kommunerna. Av resultatet kan man se skillnader på vad policyerna innehåller och hur dem används. Innehållet i trädpolicyerna är i några fall bristfällig i jämförelse med den forskning som finns kring stadsträd och viktiga värden att arbeta för. Likheter som vi kan dra slutsatser om är att alla kommuner värnar om biologisk mångfald. Genom studien har vi märkt en skillnad på att två av de granskade trädpolicyer är mer omfattade kring antal av trädens värden och målsättningar som tas upp. Användandet av policyn skiljer sig då de granskade kommunerna använder dokumentet olika, några använder det i stor utsträckning från planering till utförandeärenden och andra har dokumentet som grund för andra mer användbara dokument. Även om dokumentet används på olika sätt fyller policyn en viktig funktion eftersom dokumentet är politiskt beslutad vilket stödjer personalens arbetssätt kring vilka riktlinjer och mål man ska förhålla sig till.Our cities are growing which leads to an increase in impervious urban surfaces. The impervious urban surfaces create a warmer local climate and increased surface runoff. The harsh urban climate can make it difficult for urban trees to grow old, and further exploitation in cities risks damaging the trees. In order to create a sustainable tree population with vital trees that can contribute to reducing the local temperature and take care of stormwater runoff, municipal documents are required that prioritize the urban trees. Within municipalities, they work with various municipal documents that contribute to protecting the city's trees, one of the overarching municipal documents is tree policy. The purpose of the work is to investigate whether different municipalities tree policies are equivalent and whether they are relevant and useful documents. To answer the purpose, a document analysis and an interview study are implemented. The document analysis concerns four Swedish municipalities and in the interview study included three people who work within the municipality. The results show differences in what the policies contain and how they are used. The content of the tree policies is in some cases deficient in comparison with research that exists around urban trees and important values to work for. Similarities that we can draw conclusions about are that all municipalities contain biodiversity. Through the studies, we have noticed a difference in that the two of the reviewed tree policies are more comprehensive in terms of tree values and objectives that are addressed. The use of the policy differs as some use it extensively from planning to execution matters and others use the document as a basis for other more useful documents. Even if the document is used in different ways, the policy fulfils an important function because the document is politically decided, which supports the staff's way of working through the guidelines and goals that are stated in the policy

Epstein-Barr Virus-Encoded BARF1 Protein is a Decoy Receptor for Macrophage Colony Stimulating Factor and Interferes with Macrophage Differentiation and Activation

Epstein-Barr virus (EBV), like many other persistent herpes viruses, has acquired numerous mechanisms for subverting or evading immune surveillance. This study investigates the role of secreted EBV-encoded BARF1 protein (sBARF1) in creating an immune evasive microenvironment. Wild-type consensus BARF1 was expressed in the human 293 cell line and purified. This native hexameric sBARF1 had inhibitory capacity on macrophage colony stimulating factor (M-CSF)-stimulated, and not on granulocyte macrophage-colony stimulating factor (GM-CSF)-stimulated growth and differentiation of myeloid cells. Antibodies specific to hexameric sBARF1 were able to block this effect. M-CSF was shown to interact with sBARF1 via the protruding N-terminal loops involving Val38 and Ala84. Each BARF1 hexamer was capable of binding three M-CSF dimers. Mutations in the BARF1 loops greatly affected M-CSF interaction, and showed loss of growth inhibition. Analysis of the activation state of the M-CSF receptor c-fms and its downstream kinase pathways showed that sBARF1 prevented M-CSF-induced downstream phosphorylation. Since M-CSF is an important factor in macrophage differentiation, the effect of sBARF1 on the function of monocyte-derived macrophages was evaluated. sBARF1 affected overall survival and morphology and significantly reduced expression of macrophage differentiation surface markers such as CD14, CD11b, CD16, and CD169. Macrophages differentiating in the presence of sBARF1 showed impaired responses to lipopolysaccharide and decreased oxygen radical formation as well as reduced phagocytosis of apoptotic cells. In conclusion, EBV sBARF1 protein is a potent decoy receptor for M-CSF, hampering the function and differentiation of macrophages. These results suggest that sBARF1 contributes to the modulation of immune responses in the microenvironment of EBV-positive carcinoma

Complexes of Oligopeptides of Structure-Determining Amino Acids with Phosphotungstic Acid

Peptides tend to form anisotropic structures, being both asymmetric and chiral. Structure-determining peptides include phenylalanine (Phe) and tyrosine (Tyr) amino acids as they contain aromatic rings, which are sterically demanding and prone to self-assembly via pi-stacking. Pursuing the mechanisms of protein interactions with oxide nanoparticles, we used Keggin phosphotungstic acid polyoxometalate (POM) as a model. Six complexes of the POM with different peptide-based ligands were studied, including Phe, Ala (Alanine), and Tyr. Phe-Ala formed a layered structure with pockets of pi-stacking involving four Phe residues. Ala-Phe formed two structures based on the rate of formation. The faster forming structure had a loose pattern of POMs in columns surrounded by chains of the ligand with alternating H-bonding and pi-stacking. The slower-forming one had a denser network, also with columns of POMs, but with a more complex network of peptides, including pi-stacks of three residues appearing as a "web" rather than a "chain". Ala-Ala showed mainly H-bonding connecting the molecules, with the peptide filling the spaces between POMs rather than controlling the structure. Ala seemed to mainly act as a bridge between three POMs, and it had the effect of forming a highly porous structure reminiscent of metal-organic frameworks (MOFs). Tyr formed long columns of the amino acid with both vertical and lateral H-bonding, resulting in alternating layers of POMs and parallel Tyr columns. These structures provide insights into the interactions between biomolecules and POMs, which is valuable for the design and synthesis of POM-derived composite materials

Factors influencing stoichiometry and stability of polyoxometalate - peptide complexes

In the pursuit of understanding the factors guiding interactions between polyoxometalates (POMs) and biomolecules, several complexes between Keggin phosphomolybdate and diglycine have been produced at different acidity and salinity conditions, leading to difference in stoichiometry and in crystal structure. Principal factors determining how the POM and dipeptide interact appear to be pH, ionic strength of the medium, and the molar ratio of POM to peptide. An important effect turned out to be even the structure-directing role of the sodium cations coordinating carbonyl functions of the peptide bond. Given the interest in applying POMs in biological systems, these factors are highly relevant to consider. In the view of recent interest in using POMs as nano catalysts in peptide hydrolysis also the potential Keggin POM transformation in phosphate buffered saline medium was investigated leading to insight that nanoparticles of zirconium phosphate (ZrP) can be actual catalysts for breakdown of the peptide bond

Molecular mechanisms behind the anti corona virus activity of small metal oxide nanoparticles

The recent COVID-19 pandemic has set a strong quest for advanced understanding of possible tracks in abating and eliminating viral infections. In the view that several families of "pristine" small oxide nanoparticles (NPs) have demonstrated viricidal activity against SARS-CoV-2, we studied the effect of two NPs, with presumably different reactivity, on two viruses aiming to evaluate two "primary suspect" routes of their antiviral activity, either specific blocking of surface proteins or causing membrane disruption. The chosen NPs were non-photoactive 3.5 nm triethanolamine terminated (surface capped) titania TiO2 NPs (TATT) and ultrasmall (1.1 nm) silicotungstate polyoxometalate (POM) NPs. The former were expected to both, interact with viral surface proteins as well as strongly complex with phosphate groups whereas the latter was not expected to form surface complexes. We demonstrated that expectedly, POM NPs up to 1.25 mM (4.5 mg l(-1)) had no significant antiviral activity towards neither of the used viruses, an enveloped transmissible gastroenteritis virus (TGEV) belonging to coronaviruses and non-enveloped encelomyocarditis virus (EMCV). At the same time, TATT NPs exhibited statistically significant (p < 0.05) antiviral activity against TGEV starting from 0.125 mM (12 mu g ml(-1)). However, no antiviral activity of TATT against non-enveloped EMCV was detected. The observation that TATT NPs showed activity only against enveloped viruses and at relatively high concentrations suggests that the effect could be related with complexation with phospholipids. Possible chemical mechanism of viral membrane disruption was investigated by a variable temperature NMR study of NP complexation with model organic phosphate molecules, proving TATT to strongly interact with them and POM remain unreacted. Viral membrane disruption by TATT NPs was additionally confirmed by demonstraing RNA leackage from TGEV upon contact with those NPs. Therefore, our study proved a new mechanism of antiviral action of titania NPs in the dark which involved membrane disruption proceeding via direct surface complexation

Role of monocarboxylate transporters in human cancers : state of the art

Monocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acidresistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness