Synthesis and discovery of potent carbonic anhydrase,acetylcholinesterase, butyrylcholinesterase,and α‐glycosidase enzymes inhibitors: The novel N,N′‐bis‐cyanomethylamine and alkoxymethylamine derivatives

During this investigation, N,N′‐bis‐azidomethylamines, N,N′‐bis‐cyanomethylamine, new alkoxymethylamine and chiral derivatives, which are considered to be a new generation of multifunctional compounds, were synthesized, functional properties were investigated, and anticholinergic and antidiabetic properties of those compounds were studied through the laboratory tests, and it was approved that they contain physiologically active compounds rather than analogues. Novel N‐bis‐cyanomethylamine and alkoxymethylamine derivatives were effective inhibitors of the α‐glycosidase, cytosolic carbonic anhydrase I and II isoforms, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with K_i values in the range of 0.15–13.31 nM for α‐glycosidase, 2.77–15.30 nM for human carbonic anhydrase isoenzymes I (hCA I), 3.12–21.90 nM for human carbonic anhydrase isoenzymes II (hCA II), 23.33–73.23 nM for AChE, and 3.84–48.41 nM for BChE, respectively. Indeed, the inhibition of these metabolic enzymes has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances.     

Novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes: Synthesis,characterization, acetylcholinesterase,butyrylcholinesterase, and carbonic anhydrase inhibitory properties

The thiolation reaction was carried out in a benzene solution at 80°C and p‐substituted ketones and mercaptoacetic acid in a molar ratio (1:4) of in the presence of a catalytic amount of toluene sulfonic acids. The enzyme inhibition activities of the novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives were investigated. These novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives showed good inhibitory action against acetylcholinesterase (AChE) butyrylcholinesterase (BChE), and human carbonic anhydrase I and II isoforms (hCA I and II). AChE inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. Many clinically established drugs are carbonic anhydrase inhibitors, and it is highly anticipated that many more will eventually find their way into the market. The novel synthesized compounds inhibited AChE and BChE with K_i values in the range of 0.64–1.47 nM and 9.11–48.12 nM, respectively. On the other hand, hCA I and II were effectively inhibited by these compounds, with K_i values between 63.27–132.34 and of 29.63–127.31 nM, respectively.     

Association between presence of <Emphasis Type="Italic">Triticum timopheevii</Emphasis> introgression and D-genome retention in hexaploid/tetraploid wheat crosses

The 2G Triticum timopheevii introgression harbours genes for multiple disease resistance and quality traits in bread wheat. In order to transfer this segment from bread wheat into durum, the bread wheat line Sunguard, which carries this introgressed 2G segment was crossed with three tetraploid durum parents. A significant difference was observed in the segregation ratio of the 2G segment in the different crosses at the F₂ generation with two of the three populations indicating segregation distortion against the hexaploid 2G segment. In these populations, the presence of the 2G segment was strongly correlated with the presence of D-genome chromosomes. These results were confirmed in the F₄ generation of these populations. Six plants were identified in the F₄ generation, which had retained the introgressed 2G segment in a homozygous condition and did not have a complete D-genome set. Two of these lines only had two non-homologous D-genome chromosomes in the F₅ generation. Thus, the 2G segment and possibly other translocations can be transferred into durum wheat through hexaploid/tetraploid hybridisation.     

Genetic mapping of <Emphasis Type="Italic">psl</Emphasis> locus and quantitative trait loci for angular leaf spot resistance in cucumber (<Emphasis Type="Italic">Cucumis sativus</Emphasis> L.)

One of the most important cucumber diseases is bacterial angular leaf spot (ALS), whose increased occurrence in open-field production has been observed over the last years. To map ALS resistance genes, a recombinant inbred line (RIL) mapping population was developed from a narrow cross of cucumber line Gy14 carrying psl resistance gene and susceptible B10 line. Parental lines and RILs were tested under growth chamber conditions as well as in the field for angular leaf spot symptoms. Based on simple sequence repeat and DArTseq, genotyping a genetic map was constructed, which contained 717 loci in seven linkage groups, spanning 599.7 cM with 0.84 cM on average between markers. Monogenic inheritance of the lack of chlorotic halo around the lesions, which is typical for ALS resistance and related with the presence of recessive psl resistance gene, was confirmed. The psl locus was mapped on cucumber chromosome 5. Two major quantitative trait loci (QTL) psl5.1 and psl5.2 related to disease severity were found and located next to each other on chromosome 5; moreover, psl5.1 was co-located with psl locus. Identified QTL were validated in the field experiment. Constructed genetic map and markers linked to ALS resistance loci are novel resources that can contribute to cucumber breeding programs.     

<Emphasis Type="Italic">Espeletia</Emphasis> giant rosette plants are reliable biological indicators of time since fire in Andean grasslands

Páramo grasslands in the tropical Andes are fire-prone ecosystems and an understanding of their fire ecology is fundamental to biodiversity conservation and ecosystem management. Fire registers are normally impractical in these remote, cloud-covered landscapes, but Espeletia giant rosette plants have been proposed as biological indicators of time since fire in páramos. Espeletia giant stem rosettes tolerate fire well, protecting apical buds in at the heart of their leaf rosettes, and for some species, germination is known to be enhanced by fire. As the plant grows, its dead leaves remain attached to the stem, but fire removes these and resets the “leaf clock”. This study uses a unique register of fires in one Ecuadorian páramo to assess the robustness of this biological indicator. Dead leaf cover on Espeletia pycnophylla giant rosette plants was measured in fifteen different sites with known fire dates from 2000 to 2014. The growth rates of plants at four different elevations were measured over a 2-year period and used to estimate time since fire based on dead leaf cover in the known sites. Estimates were accurate to ± 2 year. Thus, where fire records are missing, relatively easy measurements of growth rates and dead leaf cover of Espeletia giant rosette plants can provide reliable estimates across a wide range of times since fire. This approach has value for direct investigations into fire ecology but also for studies in which controlling for fire dynamics is necessary to reveal underlying patterns. Therefore, this approach also offers a means to obtain better information on other landscape-scale processes such as the impact of climate change on biodiversity or the provision of ecosystem services.     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations and clinical interpretation in 398 ovarian cancer patients: comparison with breast cancer variants in a similar population

Background

Ovarian cancer is the leading cause of death worldwide among gynecologic malignancies. The recent approval of inhibitors of poly (ADP-ribose) polymerase (iPARP) in the treatment of ovarian cancer in the presence of a BRCA1/2 mutation has sparked the analysis of women with such diagnosis, which can further benefit from the detection of carriers in the family. Germline sequence and large rearrangements for BRCA1/2 were tested in 398 consecutive epithelial ovarian cancer (EOC) patients.The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with ovarian serous carcinoma, with a view to adequately selecting patients for prevention through family counseling and correlating this frequency with platinum sensitivity as a guidance to identify patients eligible for iPARP in our population.

Results

A total of 96 patients carried a pathogenic germline mutation, accounting for an overall 24.1% mutation incidence. Among mutation carriers, BRCA1 showed 62.5% incidence, BRCA2 rendered 36.5%, and one patient exhibited a mutation in both genes. Three pathogenic mutations were recurrent mutations detected five, three, and four times and represented 12.5% of the mutated samples. Worth highlighting, a 50% mutation incidence was detected when breast and ovarian cancer coexisted in the same patient. Novel mutations amounted to 9.4% of the total mutations, as compared to 4.7% in breast cancer. Forty out of 60 BRCA1 mutations were beyond the ovarian cancer cluster region (OCCR), in stark contrast with 22 out of 36 BRCA2 mutations being inside the OCCR. Taken together, germline BRCA1/2 mutations in EOC patients showed a distinct mutational spectrum compared to our previously published data on breast cancer patients.

Conclusions

In sum, our study provides novel data on ovarian BRCA1/2 mutation prevalence worldwide, enhances adequate patient selection for family counseling and prevention, and sheds light on the benefits of iPARP treatment.

     

Associations of high-altitude polycythemia with polymorphisms in <Emphasis Type="Italic">PIK3CD</Emphasis> and <Emphasis Type="Italic">COL4A3</Emphasis> in Tibetan populations

Background

High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet.

Aim/methods

This study aimed to explore the related hereditary factors of HAPC in the Chinese Han and Tibetan populations. A total of 140 patients (70 Han and 70 Tibetan) with HAPC and 60 healthy control subjects (30 Han and 30 Tibetan) were recruited for a case-control association study. To explore the genetic basis of HAPC, we investigated the association between HAPC and both phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta gene (PIK3CD) and collagen type IV α3 chain gene (COL4A3) in Chinese Han and Tibetan populations.

Results/conclusion

Using the unconditional logistic regression analysis and the false discovery rate (FDR) calculation, we found that eight SNPs in PIK3CD and one SNP in COL4A3 were associated with HAPC in the Tibetan population. However, in the Han population, we did not find any significant association. Our study suggested that polymorphisms in the PIK3CD and COL4A3 were correlated with susceptibility to HAPC in the Tibetan population.

     

Encapsulation of Probiotics: Proper Selection of the Probiotic Strain and the Influence of Encapsulation Technology and Materials on the Viability of Encapsulated Microorganisms

Probiotic encapsulation is an entire system that not only involves but also depends on many factors. Elements such as the encapsulation method itself, materials, environmental conditions, and last, but not least, the strain; all play an important role in the encapsulation process. The current paper focuses on the right selection of probiotics, the various stress factors that impact the survival capacity of probiotics during and after encapsulation, and the rational selection of appropriate protection strategies to overcome these factors and achieve the highest possible encapsulation efficiency under optimal conditions. This review discusses the effects of temperature, moisture content, and water activity as well as pH, oxygen, and pressure on the viabilities of microorganisms. The effect of the surface and structure of the capsules on the encapsulated microorganisms and the impact of the materials used for the encapsulation are discussed as well. Last, but not least, the importance of choosing the right bacteria is reviewed.     

Qualitative Attribution,Phenomenal Experience and Being

I argue that the physiological, phenomenal and conceptual constitute a trichotomous hierarchy of emergent categories. I claim that each category employs a distinctive type of interactive mechanism that facilitates a meaningful kind of environmental discourse. I advocate, therefore, that each have a causal relation with the environment but that their specific class of mechanism qualifies distinctively the meaningfulness of that interaction and subsequent responses. Consequently, I argue that the causal chain of physical interaction feeds distinctive value-laden constructions that are ontologically distinct for each category. Within the limitations of the interactive mechanisms of each category, increasingly sophisticated forms tend to evolve. The increase in sophistication in each category inevitably leads to the emergence of the novel mechanism particular to the next in the hierarchy. In essence, there is an emergent hierarchy of evolving categories delineated by the nature of their mechanism of environmental engagement. I argue that biochemical mechanisms have a tendency to evolve meaningfully, specifically in a way that is both qualitatively relevant and responsive to environmental particulars. I explain that these mechanisms set in play an organisational imperative that leads to the emergence of the capacity to evaluate and prioritise qualitative biochemical assimilations which, inevitably, generates a subjectively individuated experience phenomenon. I then relate this to the novel characteristics of the human perspective.