Untying Knots in Proteins

A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, one may easily retract a terminal segment of the backbone from the knotting loop and untangle the knot. At still other amino acids, the outcome of pulling can go either way. We study the dependence of the untying probability on the way the protein is grasped, the pulling speed, and the temperature. Elucidation of the mechanisms underlying this dependence is critical for a successful experimental realization of protein knot untying

Ethnobotanical and faunistic aspects in the archaeological interpretation of the 17th and 18th century coffin burials in the Basilica of the Holy Trinity in Strzelno (Kuyavia, Poland)

Botanical analyses of samples taken from four coffin burials dated to the 17th and 18th centuries, located inside the Basilica of the Holy Trinity, at the Norbertine convent in Strzelno, in Kuyavia, revealed presence of thirteen plant taxa and numerous remains of Fannia canicularis pupae found among the plant remains. The practical and decorative properties of these plants,as well as their traditional symbolic meaning and application in the burial customs, have been discussed. The study provided new information on local funeral customs and allowed for the indication of the approximate timing of each of the examined burials, significantly enriching the data obtained by archaeologists

A Guide to Targeting the Endocannabinoid System in Drug Design

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research

Predicting the order in which contacts are broken during single molecule protein stretching experiments

We combine two methods to enable the prediction of the order in which contacts are broken under external stretching forces in single molecule experiments. These two methods are Gô-like models and elastic network models. The Gô-like models have shown remarkable success in representing many aspects of protein behavior, including the reproduction of experimental data obtained from atomic force microscopy. The simple elastic network models are often used successfully to predict the fluctuations of residues around their mean positions, comparing favorably with the experimentally measured crystallographic B-factors. The behavior of biomolecules under external forces has been demonstrated to depend principally on their elastic properties and the overall shape of their structure. We have studied in detail the muscle protein titin and green fluorescent protein and tested for ten other proteins. First, we stretch the proteins computationally by performing stochastic dynamics simulations with the Gô-like model. We obtain the force–displacement curves and unfolding scenarios of possible mechanical unfolding. We then use the elastic network model to calculate temperature factors (B-factors) and compare the slowest modes of motion for the stretched proteins and compare them with the predicted order of breaking contacts between residues in the Gô-like model. Our results show that a simple Gaussian network model is able to predict contacts that break in the next time stage of stretching. Additionally, we have found that the contact disruption is strictly correlated with the highest force exerted by the backbone on these residues. Our prediction of bond-breaking agrees well with the unfolding scenario obtained with the Gô-like model. We anticipate that this method will be a useful new tool for interpreting stretching experiments

Cancer epidemiology in Poland

W pracy przedstawiono obraz epidemiologiczny nowotworów złośliwych w Polsce, jego zmiany w czasie oraz porównanie z krajami Unii Europejskiej. Przebieg trendów czasowych umieralności w głównych lokalizacjach nowotworów złośliwych w Polsce jest podobny do obrazu nowotworowego krajów UE. Transformacja epidemiologiczna umieralności z powodu nowotworów w Polsce odbywa się w stosunku do krajów Europy Zachodniej z pewnym opóźnieniem czasowym.  Ogółem trendy epidemiologiczne wszystkich lokalizacji nowotworowych są uśrednieniem rozbieżnych trendów w zachorowaniach na poszczególne nowotwory, często zdominowanym przez zmiany trendów największych lokalizacji nowotworowych. Tak dzieje się np. u mężczyzn w Polsce w przypadku umieralności na nowotwory złośliwe płuca. W drugiej części pracy poddano analizie zjawisko zachorowalności, które także wskazuje na wyraźne zróżnicowanie trendów czasowych poszczególnych lokalizacji. Trendy częstości zachorowań mierzone bezwzględną liczbą nowo diagnozowanych chorób zależą od wielu czynników — środowiskowych czynników ryzyka (np. częstości palenia), które są modyfikowalne, ale także kluczowe znaczenie mają zmiany struktury wieku populacji. Krzywa zachorowań rośnie wykładniczo wraz ze wzrostem długości życia (czynnik niemodyfikowalny). Znaczna większość (60%) zachorowań na nowotwory złośliwe jest diagnozowana wśród osób po 65 r.ż., a w Polsce obserwuje się stały przyrost ludności w tym wieku. Trzy zjawiska są najbardziej charakterystyczne dla obrazu trendów czasowych zachorowalności z powodu nowotworów złośliwych w Polsce: 1) gwałtowny spadek zachorowań z powodu nowotworów złośliwych płuca u mężczyzn (po okresie trwającego kilka dekad wzrostu zachorowań); 2) bardzo szybki wzrost zachorowań z powodu nowotworów złośliwych prostaty, szczególnie po 1990 roku; 3) dramatyczny wzrost nowo diagnozowanych nowotworów złośliwych piersi u kobiet, który zdominował zachorowalność na nowotwory złośliwe w Polsce u kobiet (obecnie co czwarty nowo diagnozowany nowotwór u kobiet to nowotwór złośliwy piersi). Dodatkowo szczegółowej analizie epidemiologicznej poddano kilka głównych lokalizacji nowotworów złośliwych (nowotwory płuca, piersi, gruczołu krokowego, jelita grubego, szyjki macicy i żołądka) oraz przedstawiono ich po­równanie z innymi krajami.  Największy sukces w kontrolowaniu nowotworów złośliwych osiągnięto w tych schorzeniach, w których możliwa jest prewencja (przede wszystkim nowotwory złośliwe płuca u mężczyzn), ale także w tych nowotworach, gdzie możliwy jest skuteczny populacyjny skrining (nowotwory złośliwe szyjki macicy, nowotwory złośliwe piersi).This paper presents the epidemiological picture of cancer in Poland, its changes over time and a comparison with other countries of the European Union (EU). The mortality time trends for the main cancer sites in Poland are similar to those observed in other EU countries. However, the epidemiological transformation in cancer mortality in Poland is delayed with respect to countries of Western Europe. The overall epidemiological trends are an average of the individual trends for different cancers, often dominated by changes in trends for the major cancer sites. This is observed, for example, in the case of male lung cancer mortality in Poland. In the second part of the study we analysed cancer morbidity, which also demonstrated clear differences in time trends in each site. Incidence trends measured by the absolute number of newly diagnosed diseases depend on many factors. The most important factor is the modifiable environmental risk factors (e.g. smoking prevalence), as well as the changes in the age structure the population. The incidence curve grows exponentially with the increase of lifespan (a non-modifiable factor). The vast majority (60%) of cancer cases are diagnosed among people over 65 years, and in Poland a steady increase of population in this age group is observed. Three phenomena emerge as the most characteristic of the time trends of cancer morbidity in Poland. (1) A sharp decline in incidence of lung cancer in men (after a period of rising incidence that lasted for decades). (2) Rapid growth in incidence of prostate cancer, especially after 1990. (3) A dramatic increase in newly diagnosed breast cancer cases in women, which dominated the incidence of cancer in women in Poland (currently one in four of newly diagnosed cancers among women is breast cancer).In addition, a detailed epidemiological analysis was conducted for several major cancer sites (lung, breast, prostate, colorectal, cervix and stomach) and its results were compared with trends observed in other countries. The biggest success in cancer control was achieved in those cancer locations, for which prevention is possible (especially lung cancer in men), and also in those cancers, where it is possible to effectively screen a population (cervical cancer, breast cancer).

Mg2+-Dependent Methyl Transfer by a Knotted Protein: A Molecular Dynamics Simulation and Quantum Mechanics Study

Mg2+ is required for the catalytic activity of TrmD, a bacteria-specific methyltransferase that is made up of a protein topological knot-fold, to synthesize methylated m1G37-tRNA to support life. However, neither the location of Mg2+ in the structure of TrmD nor its role in the catalytic mechanism is known. Using molecular dynamics (MD) simulations, we identify a plausible Mg2+ binding pocket within the active site of the enzyme, wherein the ion is coordinated by two aspartates and a glutamate. In this position, Mg2+ additionally interacts with the carboxylate of a methyl donor cofactor S-adenosylmethionine (SAM). The computational results are validated by experimental mutation studies, which demonstrate the importance of the Mg2+-binding residues for the catalytic activity. The presence of Mg2+ in the binding pocket induces SAM to adopt a unique bent shape required for the methyl transfer activity and causes a structural reorganization of the active site. Quantum mechanical calculations show that the methyl transfer is energetically feasible only when Mg2+ is bound in the position revealed by the MD simulations, demonstrating that its function is to align the active site residues within the topological knot-fold in a geometry optimal for catalysis. The obtained insights provide the opportunity for developing a strategy of antibacterial drug discovery based on targeting of Mg2+-binding to TrmD