Planning of construction projects taking into account the design risk

Complex construction projects require appropriate planning that allows for time and cost optimization, maximization of the use of available resources and appropriate investment control. Scheduling is a complicated process, due to the uncertainties and risks associated with construction works, the paper describes the development of the scheduling method traditionally used in Poland, based on data from KNR catalogs, by using the RiskyProject Professional program. In the RiskyProject Professional program, the risk and uncertainty with reference to a specific construction project were modeled, and the calculation results were compared with the real time of the project implementation. The conclusions from the work carried out confirm that the SRA (Schedule Risk Analysis) analysis of the base schedule allows for a more faithful representation of the actual conditions of a construction project. The probability of investment realization generated on the basis of the SRA analysis may be assumed at the level of 75÷90%

N-[1,3-Dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulphonamides as Novel Selective Human Cannabinoid Type 2 Receptor (hCB2R) Ligands; Insights into the Mechanism of Receptor Activation/Deactivation

Cannabinoid type 1 (hCB1) and type 2 (hCB2) receptors are pleiotropic and crucial targets whose signaling contributes to physiological homeostasis and its restoration after injury. Being predominantly expressed in peripheral tissues, hCB2R represents a safer therapeutic target than hCB1R, which is highly expressed in the brain, where it regulates processes related to cognition, memory, and motor control. The development of hCB2R ligands represents a therapeutic opportunity for treating diseases such as pain, inflammation and cancer. Identifying new selective scaffolds for cannabinoids and determining the structural determinants responsible for agonism and antagonism are priorities in drug design. In this work, a series of N-[1,3-dialkyl(aryl)-2-oxoimidazolidin-4-ylidene]-aryl(alkyl)sulfonamides is designed and synthesized and their affinity for human hCB1R and hCB2R is determined. Starting with a scaffold selected from the NIH Psychoactive Drug Screening Program Repository, through a combination of molecular modeling and structure–activity relationship studies, we were able to identify the chemical features leading to finely tuned hCB2R selectivity. In addition, an in silico model capable of predicting the functional activity of hCB2R ligands was proposed and validated. The proposed receptor activation/deactivation model enabled the identification of four pure hCB2R-selective agonists that can be used as a starting point for the development of more potent ligands

Modeling acquired resistance to the second-generation androgen receptor antagonist enzalutamide in the TRAMP model of prostate cancer

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of prostate cancer. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat prostate cancer and CRPC.Significance: Merging mathematical modeling with experimental data, this study presents the "TRAMP-based platform" as a novel experimental tool to study the in vitro and in vivo evolution of prostate cancer resistance to enzalutamide

Analysis of transforming growth factor α (TGFα) and its receptor (EGFR) expression in clear cell renal cell carcinoma.

Jasnokomórkowy rak nerki (ccRCC) jest najbardziej złośliwym nowotworem nerek. W momencie diagnozy u około 85% pacjentów występują rozległe przeczuty do innych narządów. Inaktywacja genu von Hippel - Lindau (VHL) jest główną przyczyną rozwoju jasnokomórkowego raka nerki. Upośledzenie funkcji tego białka powoduje zaburzenie degradacji czynnika indukowanego hipoksją (HIF1α), prowadząc do jego nagromadzenie w komórkach. HIFα stymuluje komórki do produkcji czynników wzrostowych takich jak: PDGF, VEGF oraz TGFα. W ten sposób uczestniczy pośrednio w aktywacji wielu szlaków sygnalizacyjnych mi. PI3K - PDK1 - AKT oraz kaskady kinaz MAP, wpływając na migrację oraz proliferację komórek.W niniejszej pracy przedstawiono wyniki badań nad poziomem ekspresji transformującego czynnika wzrostowego typu α i jego receptora (EGFR) oraz aktywacją wewnątrzkomórkowych szlaków sygnalizacyjnych w jasnokomórkowym raku nerki. Zbadano poziom fosforylacji białek takich jak: Akt, ERK, p38 oraz p65. W eksperymentach korzystano z tkanek zdrowych oraz z nowotworowych pobranych od pacjentów podczas zabiegu częściowej lub całkowitej nefrektomii. Badania wykazały różnice w poziomie ekspresji TGFα i EGFR w tkankach nowotworowych w porównaniu do tkanek zdrowych w różnych stadiach nowotworu. W tkankach nowotworowych zaobserwowano również, wzrost aktywności badanych szlaków sygnalizacyjnych.Clear cell renal cell carcinoma (ccRCC) is the most malignant kidney. About a 85% of the ccRCC patients have metastatic disease at time of diagnosis. Inactivation of the von Hippel- Lindau gene (VHL) is very common in ccRCC and leads to disorder in degradation of hypoxia inducible factor (HIF1α) and its accumulation in the cells.HIFα could stimulate cells to production of several growth factors such as PDGF, VEGF and TGFα. In this way is involved in activation of many signaling pathways ex. PI3K - PDK1- AKT and MAP kinase cascade. This work presents analysis of the level transforming growth factor type α and its receptor (EGFR) expression and intracellular signaling pathways activation in clear cell renal cell carcinoma. Examined level of proteins phosphorylation such as Akt, ERK, p38, and p65. In experiments used normal and tumor proteins isolated after partial or total nephrectomy.Studies have shown differences in the level of TGFα and EGFR expression in tumor tissue compared to normal at different stages of cancer. In tumor tissue was also observed increase activity of the cellular signaling pathways

Harmonogramowanie Probabilistyczną Metodą Sprzężeń Czasowych I (PTCM I) - założenie ciągłości pracy brygad roboczych

Modeling and numerical analysis of the design of building structures, their technology, organization and management methods of construction processes are the subject of the work of many scientists in Poland. Schedule designers try to best reflect the reality of construction projects with the available methods, although this procedure is not always successful. One of the scheduling methods is the Time Coupling Methods (TCM), which can be refined using the predictive durations of the Multivariate Method of Statistical Models (MMSM) construction processes and standard deviations. A new scheduling method in the probabilistic approach was developed - Probabilistic Time Couplings Method I (PTCM I). At PTCM I, work is organized in such a way as to maintain the continuity of work of employees, as downtime of workers is disadvantageous and costly. The total duration of the new investment was forecasted and compared with the other methods of scheduling and with real time after its completion. The results clearly show that the developed methodology can be successfully used in scheduling construction works.Modelowanie i analiza numeryczna projektowania konstrukcji budowlanych, ich technologii, organizacji i metod zarządzania procesami budowlanymi są przedmiotem pracy wielu naukowców w Polsce. Projektanci harmonogramów starają się jak najlepiej odzwierciedlić realia projektów budowlanych dostępnymi metodami, choć procedura ta nie zawsze jest skuteczna. Jedną z metod planowania jest metoda Time Coupling Methods (TCM), którą można udoskonalić za pomocą predykcyjnych czasów trwania procesów konstrukcji wielowymiarowej metody modeli statystycznych (MMSM) i odchyleń standardowych. Opracowano nową metodę szeregowania w podejściu probabilistycznym - Probabilistic Time Couplings Method I (PTCM I). W PTCM I praca jest zorganizowana w taki sposób, aby zachować ciągłość pracy pracowników, gdyż przestoje pracowników są niekorzystne i kosztowne. Prognozowano łączny czas trwania nowej inwestycji i porównano ją z innymi metodami harmonogramowania oraz z czasem rzeczywistym po jej zakończeniu. Wyniki jednoznacznie pokazują, że opracowaną metodykę można z powodzeniem zastosować w harmonogramowaniu robót budowlanych

Structure, Spectra and Photochemistry of 2-Amino-4-Methylthiazole: FTIR Matrix Isolation and Theoretical Studies

International audienceThe structure, tautomerization pathways, vibrational spectra, and photochemistry of 2-amino-4-methylthiazole (AMT) molecule were studied by matrix isolation FTIR spectroscopy and DFT calculations undertaken at the B3LYP/6-311++G(3df,3pd) level of theory. The most stable tautomer with the five-membered ring stabilized by two double C=C and C=N bonds, was detected in argon matrices after deposition. When the AMT/Ar matrices were exposed to 265 nm selective irradiation, three main photoproducts, N-(1-sulfanylprop-1-en-2-yl)carbodiimide (fp1), N-(1-thioxopropan-2-yl)carbodiimide (fp2) and N-(2-methylthiiran-2-yl)carbodiimide (fp3), were photoproduced by a cleavage of the CS–CN bond together with hydrogen atom migration. The minor photoreaction caused by the cleavage of the CS–CC bond and followed by hydrogen migration formed 2-methyl-1H-azirene-1-carbimidothioic acid (fp15). We have also found that cleavage of the CS–CN bond followed by disruption of the N–C bond produced cyanamide (fp11) and the C(CH3)=CH–S biradical that transformed into 2-methylthiirene (fp12) and further photoreactions produced 1-propyne-1-thiole (fp13) or methylthioketene (fp14). Cleavage of the CS–CC bond followed by disruption of the N–C bond produced propyne (fp22) and the S–C(NH2)=N biradical that transformed into 3-aminethiazirene (fp23); further photoreactions produced N-sulfanylcarbodiimide (fp25). As a result of these transformations, several molecular complexes were identified as photoproducts besides new molecules in the AMT photolysis process

Bacterial Protein Tyrosine Phosphatases as Possible Targets for Antimicrobial Therapies in Response to Antibiotic Resistance

The review is focused on the bacterial protein tyrosine phosphatases (PTPs) utilized by bacteria as virulence factors necessary for pathogenicity. The inhibition of bacterial PTPs could contribute to the arrest of the bacterial infection process. This mechanism could be utilized in the design of antimicrobial therapy as adjuvants to antibiotics. The review summaries knowledge on pathogenic bacterial protein tyrosine phosphatases (PTPs) involved in infection process, such as: PTPA and PTPB from Staphylococcus aureus and Mycobacterium tuberculosis; SptP from Salmonella typhimurium; YopH from Yersinia sp. and TbpA from Pseudomonas aeruginosa. The review focuses also on the potential inhibitory compounds of bacterial virulence factors and inhibitory mechanisms such as the reversible oxidation of tyrosine phosphatases

Modeling and Optimization of the Isolation of Blackcurrant and Black Cumin Seeds Oils Using Supercritical Fluid Extraction

Supercritical fluid extraction is a powerful analytical tool and it is willingly used by researchers for the isolation of various components from different matrices. In our study, the carbon dioxide in the supercritical state was used for the extraction of oils from blackcurrant and black cumin seeds. To determine the optimal conditions for the process (temperature, pressure and time), the method of statistical experiment planning and the Box–Behnken design was applied and the yield of the oils and the content of fatty acids (FAs) were taken into consideration. It has been found that an increase in pressure causes an increase in extraction yield (W), and an increase in temperature, both at constant pressure and time, does not significantly change the yield value. Optimal yield values were obtained for both materials under almost similar extraction parameters: 306 bar/ 43 min/ 50 °C (blackcurrant) and 282 bar/ 40 min/ 50 °C (black cumin). The influence of the above parameters (T, p, t) on the content of FAs in the extracts has a slightly different trend. The use of supercritical carbon dioxide for the extraction of blackcurrant and black cumin seeds allowed for high process yield and high-quality, rich in polyunsaturated fatty acids oils which can be used as a substrate or final product for industry

Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis

Osteoarthritis (OA) is a joint disease in which cartilage degenerates as a result of mechanical and biochemical changes. The main OA symptom is chronic pain involving both peripheral and central mechanisms of nociceptive processing. Our previous studies have implicated the benefits of dual- over single-acting compounds interacting with the endocannabinoid system (ECS) in OA treatment. In the present study, we focused on the specific molecular alterations associated with pharmacological treatment. OA was induced in Wistar rats by intra-articular injection of 3 mg of monoiodoacetate (MIA). Single target compounds (URB597, an FAAH inhibitor, and SB366791, a TRPV1 antagonist) and a dual-acting compound OMDM198 (FAAH inhibitor/TRPV1 antagonist) were used in the present study. At day 21 post-MIA injection, rats were sacrificed 1 h after i.p. treatment, and changes in mRNA expression were evaluated in the lumbar spinal cord by RT-qPCR. Following MIA administration, we observed 2-4-fold increase in mRNA expression of targeted receptors (Cnr1, Cnr2, and Trpv1), endocannabinoid degradation enzymes (Faah, Ptgs2, and Alox12), and TRPV1 sensitizing kinases (Mapk3, Mapk14, Prkcg, and Prkaca). OMDM198 treatment reversed some of the MIA effects on the spinal cord towards intact levels (Alox12, Mapk14, and Prkcg). Apparent regulation of ECS and TRPV1 in response to pharmacological intervention is a strong justification for novel ECS-based multi-target drug treatment in OA