Synthesis,biological evaluation,and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC₅₀ 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.     

Inflammatory Breast Cancer: The Cytokinome of Post-Mastectomy Wound Fluid Augments Proliferation,Invasion, and Stem Cell Markers

Inflammatory breast cancer (IBC) is an aggressive phenotype with a high recurrence and low survival rate. Approximately 90% of local breast cancer recurrences occur adjacent to the same quadrant as the initial cancer, implying that tumor recurrence may be caused by residual cancer cells and/or quiescent cancer stem cells (CSCs) in the tumor. We hypothesized that wound fluid (WF) collected after modified radical mastectomy (MRM) may activate cancer cells and CSCs, promoting epithelial mesenchymal transition (EMT) and invasion. Therefore, we characterized the cytokinome of WF drained from post-MRM cavities of non-IBC and IBC patients. The WF of IBC patients showed a significantly higher expression of various cytokines than in non-IBC patients. In vitro cell culture models of non-IBC and IBC cell lines were grown in media conditioned with and/without WF for 48 h. Afterwards, we assessed cell viability, the expression of CSCs and EMT-specific genes, and tumor invasion. Genes associated with CSCs properties and EMT markers were regulated in cells seeded in media conditioned by WF. IBC-WF exhibited a greater potential for inducing IBC cell invasion than non-IBC cells. The present study demonstrates the role of the post-surgical tumor cavity in IBC recurrence and metastasis.     

Evolutionary Implications of Persistence Hunting: An Examination of Energy Return on Investment for !Kung Hunting

Hominins are smaller, slower, and weaker than most large mammals, yet they have been eating meat from freshly killed large mammals since before the invention of sophisticated weaponry. It is thought that they could have achieved this seemingly impossible feat through persistence hunting, a practice powered by endurance running. Essentially, one or more hunters pursue a prey animal in the heat of the day until it reaches the point of hyperthermia. This allows a hunter to safely kill the weakened animal at close range using methods such as beating, strangling, or spearing. The energy balance of this approach to getting food is controversial and has not been calculated previously. We examined the energy costs and gains of persistence hunting through several energy returned on investment (EROI) calculations based on synthesizing available field and laboratory data on the energy used by the hunters and the energy returned from the greater kudu (Tragelaphus strepsiceros). We estimate that the EROI of these hunter-gatherers hunting a kudu ranged from 26:1 to 69:1. The net energy gained from such an effort would sustain an average sized !Kung family for 6.7 to 11.2 days. The “profit” energy within these ranges would have supported the early human societies that practiced persistence hunting, contributing to the often-noted “leisure” characterizing many foraging societies (Sahlins 1974).     

Callus induction and regeneration in sugarcane under drought stress

Tissue culture methods are useful in assessing the tolerance of various stresses due to the ease of controlling stress under in vitro conditions. This study aimed to investigate the response of sugarcane genotyps to drought stress using calli as a model system. For inducing sugarcane callus, the medium of Murashige and Skoog (MS) was used with different mannitol concentrations (100, 200, and 300 mM) to measure their effects on callus frequency, the day of callus initiation, embryogenic potential, relative growth rate (RGR), water and proline contents, K⁺ and Na⁺ contents, as well as the formation of shoot and roots for three sugarcane genotypes (e.g., GT 54-9, G 84-47, and pH 8013). The RAPD-PCR analysis was carried out using five oligonucleotide primers to identify the genetic variation among sugarcane genotypes. The results indicated that the degree of callus proliferation varied from 70 − 86%. The highest value of callus proliferation, PGR, shoot formation was recorded for the genotype GT 54-9 compared to the other two genotypes (G 84-47 and pH 8013). Calli treated with 100 mM mannitol showed the highest RGR, proline and waer contents for the genotype GT 54-9, while, those treated with 300 mM recorded the lowest values of these parameters for the genotype pH 8013. The genotype G 84-47 collected highest Na⁺ content, while the genotype pH 8013 collected highest K⁺ content. The results of this study recommend preference for GT 54-9 genotype, which is considered the most promising genotype, showing more tolerance to drought stress based on all studied traits.     

Molecular cloning of genenahH encoding extradiol-type dioxygenase from the NAH plasmid ofPseudomonas stutzeri NA1

Naphthalene-degradingPseudomonas stutzeri NA1 was found to harbour the NAH plasmid, which contains the classical upper and lower catabolic genes required for naphthalene mineralization. The lower pathway inP. stutzeri NA1 was found to proceedviameta-ring cleavage of catechol due to the presence of thenahH gene encoding extradiol catechol 2,3-dioxygenase. Naphthalene-induced cells were able to mineralise both salicylate and catechol. Absorption spectra and gas chromatography/mass spectrometry analysis ofritermediate metabolites of salicylate or catechol degradation by a crude extract ofP. stutzeri NA1 revealed the presence of themeta-ring cleavage product 2-hydroxymuconate semialdehyde as a major constituent. The extradiol ring cleavage genenahH was amplified successfully from the NAH plasmid ofP. stutzeri NA1 with catechol 2,3-dioxygenase-specific primers and cloned inEscherichia coli JM109 The complete nucleotide sequence of cloned PCR fragment was determined. Sequence analysis of cloned PCR fragment revealed an open reading frame with similarity to other extradiol dioxygenases. The deduced amino acid sequence ofnahH fromP. stutzeri NA1 showed 96% sequence identity with the catechol 2,3-dioxygenase gene fromPseudomonas putida strain H. However, when compared to othernahH genes from different pseudomonads, it was in a separate phylogenetic branch, indicating a degree of speciation among the extradiol dioxygenase family.     

Uptake of the Egyptian solar fractions in relation to fat biosynthesis by Candida parapsilosis (Wild type KSh 21)

Summary The metabolic pattern of solar in relation to the biosynthesis of different lipid groups of Candida parapsilosis (Wild type, KSh 21) was studied.The yeast showed high affinity towards hydrocarbons with short chain length. Within 2 days, about 39% of the starting hydrocarbon had been utilized by the yeast, although the addition of caproic acid to the culture medium retarded the rate of uptake of different hydrocarbons until it was itself absorbed.Addition of caproic acid also increased the triglycerides, sterol esters and phospholipid content of the cellular lipid. Cellular sterols, on the other hand, showed inferior results.Tridecanoic acid was one of the main acids obtained after 2 days of incubation.Dedicated to Professor Dr. Hans-Jürgen Rehm on the occassion of his 60th birthday     

Vertical transmission in feather mites: insights into its adaptive value

1. The consequences of symbiont transmission strategies are better understood than their adaptive causes. 2. Feather mites are permanent ectosymbionts of birds assumed to be transmitted mainly vertically from parents to offspring. The transmission of Proctophyllodes doleophyes Gaud (Astigmata, Proctophyllodidae) was studied in two European populations of pied flycatchers, Ficedula hypoleuca Pallas (Passeriformes, Muscicapidae). 3. The vertical transmission of this mite species is demonstrated here with an acaricide experiment. This study also compared (for two distant populations during 4 years) patterns in reductions in mite intensity in adult birds, from egg incubation to chick‐rearing periods, with the predictions of three hypotheses on how host survival prospects and mite intraspecific competition might drive feather mites' transmission strategy. 4. The results are in agreement with previous studies and show that feather mites transmit massively from parents to chicks. 5. The magnitude of the transmission was closer to that predicted by the hypothesis based on intraspecific competition, while a bet‐hedging strategy is also partially supported.     

A Note on the Estimation of Coverage Errors in Demographic Data

A simple formula for the lower bound of coverage errors in demographic data is obtained. The formula is derived under general assumptions, the validity of which is discussed. Three numerical examples are given.