The Risk Function of Breast and Ovarian Cancers in the Avrami-Dobrzynski Cellular Phase-Transition Model.

Specifying the role of genetic mutations in cancer development is crucial for effective screening or targeted treatments for people with hereditary cancer predispositions. Our goal here is to find the relationship between a number of cancerogenic mutations and the probability of cancer induction over the lifetime of cancer patients. We believe that the Avrami-Dobrzynski biophysical model can be used to describe this mechanism. Therefore, clinical data from breast and ovarian cancer patients were used to validate this model of cancer induction, which is based on a purely physical concept of the phase-transition process with an analogy to the neoplastic transformation. The obtained values of model parameters established using clinical data confirm the hypothesis that the carcinogenic process strongly follows fractal dynamics. We found that the model's theoretical prediction and population clinical data slightly differed for patients with the age below 30 years old, and that might point to the existence of an ancillary protection mechanism against cancer development. Additionally, we reveal that the existing clinical data predict breast or ovarian cancers onset two years earlier for patients with BRCA1/2 mutations.

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aß42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid ß fibrils, which is extremely important for applications in Alzheimer's disease therapy.

Dispersion-enabled control of photonic density of states in photonic hypercrystals.

In this work, we investigate possibility of engineering photonic density of states (PDOS) in photonic hypercrystals (PHCs). In the course of our analysis, we have demonstrated that it is possible to obtain photonic bandgap for selected polarization of light as well as to achieve significant broadband PDOS enhancement. We have also presented for the first time that anomalous dispersion, that arises from effective resonance of hyperbolic medium constituting the PHC structure, may lead to negative PDOS, which is photonic equivalent of mobility gap, observed in electronic crystals. Furthermore, we have demonstrated that application of PHC structure, instead of standalone hyperbolic medium, allows to obtain more versatile electromagnetic response, such as broadband perfect absorption of adjustable spectral range of operation.

A tetrahydroacridine derivative and its conjugate with gold nanoparticles: promising agents for the treatment of Alzheimer's disease.

A new tetrahydroacridine derivative (CHDA) with acetylcholinesterase inhibitory properties was synthesized. Using a range of physicochemical techniques, it was shown that the compound strongly adsorbs onto the surface of planar macroscopic or nanoparticulate gold, forming a nearly full monolayer. The adsorbed CHDA molecules reveal well-defined electrochemical behavior, being irreversibly oxidized to electroactive species. The CHDA also exhibits strong fluorescence, which is effectively quenched after adsorption onto gold via a static quenching mechanism. Both CHDA and its conjugate reveal considerable inhibitory properties against acetylcholinesterase activity, which is promising from the perspective of therapeutic application in the treatment of Alzheimer's disease. Moreover, both agents appear to be non-toxic as demonstrated using in vitro studies. On the other hand, conjugation of CHDA with nanoradiogold particles (Au-198) offers new potential diagnostic perspectives in medical imaging.

Mitoquinone Alleviates Donation after Cardiac Death Kidney Injury during Hypothermic Machine Perfusion in Rat Model.

Transplanted organs are subjected to harmful conditions through stopping blood flow, hypothermic storage of the graft, and subsequent reperfusion. In particular, kidneys donated from patients after cardiac arrest (DCD) are classified as more vulnerable to ischemia-reperfusion injury (IRI). Hypothermic machine perfusion is proposed as a solution for better kidney storage before transplantation, and it is a good platform for additional graft treatment. Antioxidants have gained interest in regenerative medicine due to their ability to scavenge reactive oxygen species (ROS), which play a key role in IRI. We evaluated the effect of Mitoquinone (MitoQ), a strong mitochondria-targeted antioxidant, administered directly to the perfusing buffer. Rat kidneys were isolated, randomly classified into one of the following groups, donation after brainstem death (DBD), DCD, and DCD with MitoQ, and perfused for 22 hours with a hypothermic machine perfusion system. Subsequently, we detected levels of kidney injury (KIM-1) and oxidative stress (ROS/RNS, cytochrome C oxidase, and mitochondrial integrity) markers. We compared the activation of the apoptosis pathway (caspase 3 and 9), the concentration of phosphorylated Akt (pAkt), and the pAkt/total Akt ratio. MitoQ reduces KIM-1 concentration, total ROS/RNS, and the level of caspases. We observed a decrease in pAkt and the pAkt/total Akt ratio after drug administration. The length of warm ischemia time negatively impacts the graft condition. However, MitoQ added to the perfusing system as an 'on pump' therapy mitigates injury to the kidney before transplantation by inhibiting apoptosis and reducing ROS/RNS levels. We propose MitoQ as a potential drug for DCD graft preconditioning.

Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes.

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI.

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.

Klotho protein contributes to cardioprotection during ischaemia/reperfusion injury.

Restoration of blood flow to ischaemic heart inflicts ischaemia/reperfusion (I/R) injury, which manifests in metabolic and morphological disorders. Klotho is a protein with antioxidative and antiapoptotic activity, and is involved in the regulation of inflammation and fibrosis. The aim of the current research was to determine the role of Klotho in the heart subjected to I/R injury, as well as to study Klotho as a potential cardioprotective agent. Human cardiomyocytes and Wistar rat hearts perfused using Langendorff method subjected to I/R have been used. Hemodynamic parameters of heart function, markers of I/R injury, and gene and protein expression of Klotho were measured. Human cardiomyocytes were also incubated in the presence of recombinant Klotho protein, and the viability of cells was measured. There was a higher expression of Klotho gene and protein synthesis in the cardiomyocytes subjected to I/R injury. The compensatory production and release of Klotho protein from cardiac tissue during I/R were also shown. The treatment of cardiomyocytes subjected to I/R with Klotho protein resulted in increased viability and metabolic activity of cells. Thus, Klotho contributes to compensatory mechanism during I/R, and could be used as a marker of injury and as a potential cardiopreventive/cardioprotective agent.

Controllable intermodal coupling in waveguide systems based on tunable hyperbolic metamaterials.

In this work, we study intermodal coupling in a waveguiding system composed of a planar dielectric waveguide and a tunable hyperbolic metamaterial waveguide based on graphene, which has not been yet investigated in this class of waveguide system. For this purpose, using the Lorentz reciprocity theorem, we derive coupled mode equations for the considered waveguiding system. We demonstrate, for the first time, possibility of a fully controlled power exchange between TM modes of the dielectric waveguide and both forward and backward TM modes of the hyperbolic metamaterial waveguide by changing Fermi potential of graphene. In the course of our analysis, we also investigate how the system parameters, such as waveguide width and separation distance, influence the strength of intermodal coupling.

Tissue Expression of Atrial and Ventricular Myosin Light Chains in the Mechanism of Adaptation to Oxidative Stress.

Ischemia/reperfusion (I/R) injury induces post-translational modifications of myosin light chains (MLCs), increasing their susceptibility to degradation by matrix metalloproteinase 2 (MMP-2). This results in the degradation of ventricular light chains (VLC1) in heart ventricles. The aim of the study was to investigate changes in MLCs content in the mechanism of adaptation to oxidative stress during I/R. Rat hearts, perfused using the Langendorff method, were subjected to I/R. The control group was maintained in oxygen conditions. Lactate dehydrogenase (LDH) activity and reactive oxygen/nitrogen species (ROS/RNS) content were measured in coronary effluents. Atrial light chains (ALC1) and ventricular light chains (VLC1) gene expression were examined using RQ-PCR. ALC1 and VLC1 protein content were measured using ELISA tests. MMP-2 activity was assessed by zymography. LDH activity as well as ROS/RNS content in coronary effluents was higher in the I/R group (p = 0.01, p = 0.04, respectively), confirming heart injury due to increased oxidative stress. MMP-2 activity in heart homogenates was also higher in the I/R group (p = 0.04). ALC1 gene expression and protein synthesis were significantly increased in I/R ventricles (p < 0.01, 0.04, respectively). VLC1 content in coronary effluents was increased in the I/R group (p = 0.02), confirming the increased degradation of VLC1 by MMP-2 and probably an adaptive production of ALC1 during I/R. This mechanism of adaptation to oxidative stress led to improved heart mechanical function.

Cardioprotective effect of MMP-2-inhibitor-NO-donor hybrid against ischaemia/reperfusion injury.

Hypoxic injury of cardiovascular system is one of the most frequent complications following ischaemia. Heart injury arises from increased degradation of contractile proteins, such as myosin light chains (MLCs) and troponin I by matrix metalloproteinase 2 (MMP-2). The aim of the current research was to study the effects of 5-phenyloxyphenyl-5-aminoalkyl nitrate barbiturate (MMP-2-inhibitor-NO-donor hybrid) on hearts subjected to ischaemia/reperfusion (I/R) injury. Primary human cardiac myocytes and Wistar rat hearts perfused using Langendorff method have been used. Human cardiomyocytes or rat hearts were subjected to I/R in the presence or absence of tested hybrid. Haemodynamic parameters of heart function, markers of I/R injury, gene and protein expression of MMP-2, MMP-9, inducible form of NOS (iNOS), asymmetric dimethylarginine (ADMA), as well as MMP-2 activity were measured. Mechanical heart function, coronary flow (CF) and heart rate (HR) were decreased in hearts subjected to I/R Treatment of hearts with the hybrid (1-10 µmol/L) resulted in a concentration-dependent recovery of mechanical function, improved CF and HR. This improvement was associated with decreased tissue injury and reduction of synthesis and activity of MMP-2. Decreased activity of intracellular MMP-2 led to reduced degradation of MLC and improved myocyte contractility in a concentration-dependent manner. An infusion of a MMP-2-inhibitor-NO-donor hybrid into I/R hearts decreased the expression of iNOS and reduced the levels of ADMA. Thus, 5-phenyloxyphenyl-5-aminoalkyl nitrate barbiturate protects heart from I/R injury.

Water Nanodroplet on a Hydrocarbon "Carpet"-The Mechanism of Water Contact Angle Stabilization by Airborne Contaminations on Graphene, Au, and PTFE Surfaces.

Wetting is very common phenomenon, and it is well documented that the wettability of a solid depends on the surface density of adsorbed airborne hydrocarbons. This "hydrocarbon hypothesis" has been experimentally confirmed for different surfaces, for example, graphene, TiO2, and SiO2; however, there are no scientific reports describing the influence of airborne contaminants on the water contact angle (WCA) value measured on the polytetrafluoroethylene (PTFE) surface. Using experimental data showing the influence of airborne hydrocarbons on the wettability of graphene, gold and PTFE by water, together with Molecular Dynamics simulation results we prove that the relation between the WCA and the surface concentration of hydrocarbons ( n-decane, n-tridecane, and n-tetracosane) is more complex than has been assumed up until now. We show, in contrast to commonly approved opinion, that adsorbed hydrocarbons can increase (graphene, Au) or decrease (PTFE) the WCA of a nanodroplet sitting on a surface. Using classical thermodynamics, a simple theoretical approach is developed. It is based on two adsorbed hydrocarbon states, namely, "carpet" and "dimple". In the "carpet" state a uniform layer of alkane molecules covers the entire substrate. In contrast, in the "dimple" state, the preadsorbed layer of alkane molecules covers only the open surface. Simple thermodynamic balance between the two states explains observed experimental and simulation results, forming a good starting point for future studies.

Multiresonance response in hyperbolic metamaterials.

In this paper we demonstrate a new class of anisotropic 1D hyperbolic metamaterials (HMMs) possessing multiresonant dispersion characteristics. With the help of an EMT-based model, we analyze HMMs with unit cells composed of layers characterized by various plasma frequencies, revealing multiple resonance transitions corresponding to the critical absorptions points. In particular, we show that relative locations of plasma frequencies of constituent materials and the unit cell's geometry determine the type of dispersion characteristics as well as spectral locations of critical absorption points. It is shown that a multispectral low-loss highly dispersive medium is achieved in a structure comprising layers of closely located plasma resonances. Moreover, we present that pure metallic multilayer structure can exhibit hyperbolic dispersion. The obtained results possess a significant potential in applications where a multispectral character is required, including phase matching, multiple-point perfect absorption, as well as diffractionless imaging and focusing.

Tunable spectral and spatial filters for the mid-infrared based on hyperbolic metamaterials.

In this paper we present the possibility of shaping the reflectivity characteristics of tunable hyperbolic metamaterials (THMMs). Using the example of voltage-sensitive graphene-based structures, we demonstrate the existence of spectral and spatial functionalities of edge and narrowband filters, controlled dynamically over a 3-5 µm spectral range, that are important for both civilian and military applications. We also demonstrate that the adoption of apodization techniques in the THMM design leads to a reduction in the sidelobe's parasitic effect in edge filters, as well as providing the means to reshape the overall reflectivity characteristics, which not only unveiled the tunable angle aperture functionality but also significantly increased the potential for tailoring optical properties of THMM nanostructures in general.

The role of the gynaecologist in the promotion and maintenance of oral health during pregnancy.

OBJECTIVES: The aim of the study was to assess routine dental examination attendance of pregnant women and a possible impact of gynaecological referrals on the attendance rate. MATERIAL AND METHODS: An electronic survey was conducted that was inclusive of women up to 5 years following delivery. The questions related to socio-demographic data, the course of pregnancy and childbirth, and visits to dental office during pregnancy. For statistical analysis, the authors utilized the chi-square test, Spearman's rank correlation coefficient and odds ratios. A significance level of 0.05 has been assumed. RESULTS: A total of 3455 questionnaires were analyzed encompassing women aged 13.1-45.4 years. The respondents were on average 1.78 ± 1.44 years after childbirth. The population comprises of women in 59.1% from large cities, in 74.8% with higher education and in 41% with good socio-economic status. A total of 62.3% of women from the study population have visited a dentist for a routine dental examination. Gynaecologists have given a simple referral to a dentist to 17.6% of all women. 45.9% of them were further requested to provide back the feedback of their dental consultation. Dental appoint-ments were upheld by 87.3% of referred women and by 56.9% of those without a referral (OR = 5.20 (4.05-6.67); p < 0.001). Among those who were referred, dental appointments were upheld in 91.7% of cases when further asked to provide oral health feedback and in 83.5% of cases in absence of such further request (OR = 2.19 (1.3-3.66); p = 0.003). CONCLUSIONS: It was determined that referrals from a gynaecologist, and associated oral health feedback requests increase the frequency of abiding to dental appointments during pregnancy. As such, it is necessary to increase the involvement of gynaecologists in the promotion and maintenance of perinatal oral health.

Tunable slow light in graphene-based hyperbolic metamaterial waveguide operating in SCLU telecom bands.

The tunability of slow light in graphene-based hyperbolic metamaterial waveguide operating in SCLU telecom bands is investigated. For the first time it has been shown that proper design of a GHMM structure forming waveguide layer and the geometry of the waveguide itself allows stopped light to be obtained in an almost freely selected range of wavelengths within SCLU bands. In particular, the possibility of controlling light propagation in GHMM waveguides by external biasing has been presented. The change of external electric field enables the stop light of the selected wavelength as well as the control of a number of modes, which can be stopped, cut off or supported. Proposed GHMM waveguides could offer great opportunities in the field of integrated photonics that are compatible with CMOS technology, especially since such structures can be utilized as photonic memory cells, tunable optical buffers, delays, optical modulators etc.

Control of gain/absorption in tunable hyperbolic metamaterials.

In this paper, the possibility of shaping the gain/absorption spectrum in tunable hyperbolic metamaterial (THMM) composed of subsequent layers of graphene and active/passive material by external biasing is demonstrated. For the first time it has been shown that resonance transitions between different dispersion regimes, i.e., Type I HMM→elliptic, elliptic→Type II HMM, elliptic→Type I HMM, are accompanied by interesting optical effects, such as anisotropic effective gain/absorption enhancement or electromagnetic transparency, all controllable by external voltage. We believe that this kind of tunable metamaterial could lay the foundation for a new class of active/passive media with controllable gain/absorption or electromagnetic transparency.

An infection of human adenovirus 31 affects the differentiation of preadipocytes into fat cells, its metabolic profile and fat accumulation.

The primary issue undertaken in this study was to test the hypothesis that preadipocytes would have intrinsically elevated propensity to differentiate into mature adipocytes due to HAdV31 infection. To prove that, the metabolic and molecular mechanisms responsible for HAdV31-induced adipogenesis were examined. 3T3L1 cells (mouse embryonic fibroblast, adipose like cell line) were used as a surrogate model to analyze an increased proliferation, differentiation, and maturation of preadipocytes infected with human adenovirus. An expression of E4orf1, C/EBP-ß, PPAR-γ, GAPDH, aP2, LEP, and fatty acid synthase genes, intracellular lipid accumulation as well as cytokine release from the fat cells were assessed. Data showed that HAdV31 increased an expression of C/EBP-ß and PPAR-γ genes leading to an enhanced differentiation of preadipocytes into fat cells. Besides, overexpression of GAPDH and fatty acid synthase, and decreased expression of leptin caused an increased accumulation of intracellular lipids. Secretion of TNF-α and IL-6 from HAdV31-infected cells was strongly decreased, leading to unlimited virus replication. The results obtained from this study provided the evidences that HAdV31, likewise previously documented HAdV36, is a subsequent human adenovirus affecting the differentiation and lipid accumulation of 3T3L1 cells.

Tunable graphene-based hyperbolic metamaterial operating in SCLU telecom bands.

The tunability of graphene-based hyperbolic metamaterial structure operating in SCLU telecom bands is investigated. For the first time it has been shown that for the proper design of a graphene/dielectric multilayer stack, the HMM Type I, Epsilon-Near-Zero and Type II regimes are possible by changing the biasing potential. Numerical results reveal the effect of structure parameters such as the thickness of the dielectric layer as well as a number of graphene sheets in a unit cell (i.e., dielectric/graphene bilayer) on the tunability range and shape of the dispersion characteristics (i.e., Type I/ENZ/Type II) in SCLU telecom bands. This kind of materials could offer a technological platform for novel devices having various applications in optical communications technology.

Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3-hydroxymelatonin in rice (Oryza sativa).

Melatonin is metabolized in animals to cyclic 3-hydroxymelatonin (3-OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3-OHM in animals suggests the possible presence of 3-OHM in plants. Prior to the identification of 3-OHM in plants, we directly cloned the corresponding gene(s) responsible for 3-OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2-oxoglutarate-dependent dioxygenase (2-ODD) superfamily from rice. Three of 35 E. coli library strains supplemented with 1 mmol/L melatonin were found to produce 3-OHM in their extracellular medium, suggestive of three 2-ODD genes involved in 3-OHM production. The purified recombinant 2-ODD 11, 2-ODD 26, and 2-ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3-OHM, with 2-ODD 11 showing the highest melatonin 3-hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5 mmol/L melatonin produced 3-OHM [233 µg/g fresh weight (FW)], 2-hydroxymelatonin (21 µg/g FW), and N1 -acetyl-N2 -formyl-5-methoxykynuramine (5 µg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles.