Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR

A time-temperature integrator based on fluorescent and polymorphic compounds

Despite the variety of functional properties of molecular materials, which make them of interest for a number of technologies, their tendency to form inhomogeneous aggregates in thin films and to self-organize in polymorphs are considered drawbacks for practical applications. Here, we report on the use of polymorphic molecular fluorescent thin films as time temperature integrators, a class of devices that monitor the thermal history of a product. The device is fabricated by patterning the fluorescent model compound thieno(bis)imide-oligothiophene. The fluorescence colour of the pattern changes as a consequence of an irreversible phase variation driven by temperature, and reveals the temperature at which the pattern was exposed. The experimental results are quantitatively analysed in the range 20–200°C and interpreted considering a polymorph recrystallization in the thin film. Noteworthy, the reported method is of general validity and can be extended to every compound featuring irreversible temperature-dependent change of fluorescence

Bicolor Pixels from a Single Active Molecular Material by Surface-Tension-Driven Deposition†

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Entangling quantum-logic gate operated with an ultrabright semiconductor single-photon source

We demonstrate the unambiguous entangling operation of a photonic quantum-logic gate driven by an ultrabright solid-state single-photon source. Indistinguishable single photons emitted by a single semiconductor quantum dot in a micropillar optical cavity are used as target and control qubits. For a source brightness of 0.56 photons per pulse, the measured truth table has an overlap with the ideal case of 68.4 +/- 0.5%, increasing to 73.0 +/- 1.6% for a source brightness of 0.17 photons per pulse. The gate is entangling: At a source brightness of 0.48, the Bell-state fidelity is above the entangling threshold of 50% and reaches 71.0 +/- 3.6% for a source brightness of 0.15

Cat-Owner Relationship and Cat Behaviour : Effects of the COVID-19 Confinement and Implications for Feline Management

The aim of this study was to explore the effects of the Italian COVID-19 lockdown on the cat-owner relationship and on cat behaviour. In order to do so, we used a questionnaire to obtain information on the owner and cat's demographics, living environment, cat behaviour, and possible changes in some aspects of the cat-owner relationship. The questionnaire was distributed online when the lockdown was still ongoing and was completed by 548 cat owners, mainly women. Our findings suggest that the greater amount of time that owners spent at home with their cats, as a consequence of the social restrictions, had a positive effect on the owner's perception of their relationship with their cat (e.g., higher frequency of interaction, greater emotional closeness, reduced perceived costs of caring for the cat). Similarly, the lockdown seemed to have improved the welfare of many cats, as suggested by the positive changes in many of their behaviours, even for those cats with pre-existing behavioural problems. Overall, our findings suggest that the lockdown provided many cats with a more thriving physical and social environment. They also highlight the need to reconsider some cat management practices commonly implemented in non-exceptional circumstances. The restrictive measures implemented to stem the spread of COVID-19 abruptly changed the lives of many cats and their owners. This study explored whether the lockdown in Italy affected the cat-owner relationship, as well as cat behaviour and welfare. A survey that included questions on owner and cat's demographics, living environment, cat behaviour and a modified version of the Cat/Dog Relationship Scale (C/DORS) was distributed online during the lockdown and was completed by 548 cat owners, mainly women (81.6%). With regard to the C/DORS subscales, both emotional closeness and cat-owner interactions increased during confinement, as opposed to a reduction in perceived costs. The effect of the type of job, family role and owner's age on the C/DORS scores suggests that the relationship improved for those owners that, due to the lockdown, increased the time spent with their cats. For 58.8% of respondents, their cat's general behaviour did not change, but when changes occurred, they were mostly positive (20.4%). Attention-seeking and demanding behaviours were the most increased during lockdown (25.7%). Cats with pre-existing problematic behaviours tended to either remain stable or improve during confinement. The overall positive effects of lockdown-related environmental changes on a cat's behaviour suggest that some aspects of commonly implemented cat management practices should be revised to improve cat welfare in normal circumstances

Chemical abundances of 1111 FGK stars from the HARPS GTO planet search program.Galactic stellar populations and planets

We performed a uniform and detailed abundance analysis of 12 refractory elements (Na, Mg, Al, Si, Ca, Ti, Cr, Ni, Co, Sc, Mn and V) for a sample of 1111 FGK dwarf stars from the HARPS GTO planet search program. 109 of these stars are known to harbour giant planetary companions and 26 stars are hosting exclusively Neptunians and super-Earths. The main goals of this paper are i) to investigate whether there are any differences between the elemental abundance trends for stars of different stellar populations; ii) to characterise the planet host and non-host samples in term of their [X/H]. The extensive study of this sample, focused on the abundance differences between stars with and without planets will be presented in a parallel paper. The equivalent widths of spectral lines are automatically measured from HARPS spectra with the ARES code. The abundances of the chemical elements are determined using a LTE abundance analysis relative to the Sun, with the 2010 revised version of the spectral synthesis code MOOG and a grid of Kurucz ATLAS9 atmospheres. To separate the Galactic stellar populations we applied both a purely kinematical approach and a chemical method. We found that the chemically separated (based on the Mg, Si, and Ti abundances) thin and thick discs are also chemically disjunct for Al, Sc, Co and Ca. Some bifurcation might also exist for Na, V, Ni, and Mn, but there is no clear boundary of their [X/Fe] ratios. We confirm that an overabundance in giant-planet host stars is clear for all the studied elements.We also confirm that stars hosting only Neptunian-like planets may be easier to detect around stars with similar metallicities as non-planet hosts, although for some elements (particulary alpha-elements) the lower limit of [X/H] are very abrupt.Comment: 14 pages, 12 figures, 6 tables. accepted for publication in Astronomy & Astrophysic

1601d Hazard determinants of carbon nanotubes (cnts) driving molecular initiating events (mies) in adverse outcome pathways (aops) of airways diseases

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Language Usage Conditions of Multilingual Nations - Sri Lanka“Sinhalese native speakers and Tamil native speakers\u27 scenes, their word usage conditions in Western Province and Uva Province .

Sri Lanka is a multilingual nation, where various languages, races, and religions exist. Sinhalese, Muslims and Tamils reside together with Burger, Marais and native people called ‘Veddah\u27. Sri Lankan people use three languages; Sinhala, English, and Tamil in their daily communication. To examine the language situation in Sri Lanka means to analyze the cultural and social circumstances within Sri Lanka.In particular the Code Switching (CS) is seen in various situations in Sri Lanka. It is expected that a person would switch the language code depending on the situation. This also differs according to various circumstances such as speaker\u27s life style and living conditions at home, academic background and the social hierarchy. Furthermore, it is estimated that differences in CS between Tamil minority and Sinhala majority would exist. It is important to consider these points in order to examine the situation of communication. English is also used quite often in Sri Lanka. The influence and the necessity of English would be examined through a survey of English usage spreading in the real world.The questionnaire style survey has been conducted and it was administered based on pilot research in Japan. It is necessary to investigate various circumstances that people face in order to examine the true language usage conditions. The investigation considered people in various places and situations throughout Sri Lanka.Sri Lanka consists of nine states. The research was done in eight states: Central Province, Eastern Province, Northern Province, Southern Province, Western Province North western Province, Uva Province and Sabaragamuwa province.The research was done as follows:The locations : at a house of a standard family, at a bank, at a school and at a postoffice in each locations.The subjects : 525 people including students, office workers, house-wives, farmers,and elderly people.The format of investigation: The questionnaire included four communication situations and questionsIn this paper, the language usage conditions of Sinhalese native speakers and the Tamil native speakers of both Western Province and Uva Province are analyzed in various situations. As the result, the Sinhalese native speakers in Western Province showed many examples of code switching between Sinhalese and English. Moreover, English code switching was seen frequently in the home.When considering the Uva Province, the Sinhalese native speakers use both Sinhala and English while a significant proportion of them are trilingual speakers there. They often change between the three main languages; Sinhala, English and Tamil are used quite often at schools, offices, hospitals, and so on.To examine a number of communication scenes in different language groups in Sri Lanka, it was clearly seen that there are more trilingual speakers among Tamil native speakers who more likely to switch between three languages in different situations, while Sinhalese speakers switch between two languages. The data of the survey also showed that the usage of languages varies according to the speakers\u27 social status, region where he or she lives, academic background, age, etc.Moreover, when the communication is taking place at home, the Sinhalese native speakers often use the code switching between Sinhalese and English. However, the elderly people in Sri Lanka, especially people living in Uva Province, rarely speak English due to their poor academic background.It has become clear that the language usage conditions differ from one another depending on the society, the region, and the educational level, and age of the person in Sri Lanka.However it is not well known yet when and how the code switching happens. As for code switching between English and Sinhalese, it is important to record their natural conversation in various scenes to analyze certain characteristics of the code switching. This would help clarify how Sri Lankans use these languages.千葉大学大学院人文社会科学研究科研究プロジェクト報告書第239集「ユーラシアの多言語社会と言語政策」中川裕 編Eurasian Multilingual Society and Language Policy Report on Research Project No.23

Surface induces different crystal structures in a room temperature switchable spin crossover compound

We investigated the influence of surfaces in the formation of different crystal structures of a spin crossover compound, namely [Fe(L)2] (LH: (2-(pyrazol-1-yl)-6-(1H-tetrazol-5-yl)pyridine), which is a neutral com- pound thermally switchable around room temperature. We observed that the surface induces the for- mation of two different crystal structures, which exhibit opposite spin transitions, i.e. on heating them up to the transition temperature, one polymorph switches from high spin to low spin and the second poly- morph switches irreversibly from low spin to high spin. We attributed this inversion to the presence of water molecules H-bonded to the complex tetrazolyl moieties in the crystals. Thin deposits were investi- gated by means of polarized optical microscopy, atomic force microscopy, X-ray diffraction, X-ray absorption spectroscopy and micro Raman spectroscopy; moreover the analysis of the Raman spectra and the interpretation of spin inversion were supported by DFT calculations