HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation

The human papillomavirus (HPV) type 16 E7 oncogene is critical to carcinogenesis and highly conserved. Previous studies identified a preponderance of non-synonymous E7 variants amongst HPV16-positive cancer-free controls compared to those with cervical cancer. To investigate the function of E7 variants, we constructed full-length HPV16 E7 genes and tested variants at positions H9R, D21N, N29S, E33K, T56I, D62N, S63F, S63P, T64M, E80K, D81N, P92L, and P92S (found only in controls); D14E, N29H (CIN2), and P6L, H51N, R77S (CIN3). We determined the steady-state level of cytoplasmic and nuclear HPV16 E7 protein. All variants from the controls showed a reduced level of steady-state E7 protein, with 7/13 variants having deficient protein levels. In contrast, 2/3 variants from the CIN3 precancer group had near-normal E7 levels. We assayed the activity of representative variants in stably transfected NIH3T3 cells. The H9R, E33K, P92L, and P92S variants found in control subjects had lower transforming activity than D14E and N29H variants (CIN2); and the R77S (CIN3) had activity only slightly reduced from wildtype E7. In addition, R77S and WT E7 caused increased migration of NIH3T3 cells in a wound-healing assay as compared with H9R, E33K, P92L, and P92S (controls) and D14E (CIN2). These data provide evidence that the E7 variants found in HPV16-positive cancer-free women are partially defective for transformation and cell migration further demonstrating the importance of fully active E7 in clinical cancer development.

Non-enzymatic Transformation of Aflatoxin B1 by Pseudomonas geniculata m29

Aflatoxin B1 (AFB1) is the most harmful mycotoxin produced by filamentous fungi and presents a serious threat to human and animal health. Therefore, it is essential to protect humans and animals from AFB1-induced acute and chronic toxicity. In this study, Pseudomonas strain m29 having a high efficiency of AFB1 transformation was isolated from soil. The transformation ratio by m29 was more than 97% within 24 h, and the optimum temperature for transformation was 37°C. Moreover, the AFB1 transforming activity was mainly attributed to the cell-free supernatant of strain m29. The metabolite that plays a crucial role in AFB1 transformation is likely 1,2-dimethylhydrazine or 1,1-dimethylhydrazine, as identified by GC-MS and LC-MS analysis. AFB1 was transformed into a product with molecular formula C17H14O7. To the best of our knowledge, this is the first study of non-enzymatic AFB1 transformation by bacteria. Importantly, this AFB1 transformation mechanism could be universal to various microorganisms.

The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

Genetic Screening for Potential New Targets in Chronic Myeloid Leukemia Based on Drosophila Transgenic for Human BCR-ABL1

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the Breakpoint Cluster Region (BCR) sequence and the Abelson (ABL1) gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the gmrGal4,UAS-BCR-ABL1 4M/TM3 transgenic Drosophila as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression.

Transforming Activity Groups to Business Units - Emerging Fisherwomen Managers in Kerala, India

The fisheries sector in Kerala, on account of its management initiatives on fisheries sustainability and fisher welfare, posses a unique example for the other coastal states. The state has pioneered many novel management measures and fisher welfare programmes which led to commendable socio-economic standards comparable even with the Western world. Post Tsunami during 2004 in Kerala wreathed havoc in terms of inventory and human losses which led to the initiation of Society for Assistance to fisherwomen (SAF) under the umbrella of Department of Fisheries, Government of Kerala. Over the years SAF planned and implemented many flagship programmes among which Theeramythri was instrumental in empowering women. Currently, there are more than 1200 units providing meaningful employment to more than 5000 women. The fisher empowerment improved considerably post joining SAF from 0.41to 0.64. The empowerment determinants included economical (30.7%), legal (22.81%), political (20.18%) social (14.91%) and psychological (11.4%). SAF envisioned transforming these groups from a mere activity group into viable business units with more financial outlays, repayments, commitment at self-sufficiency, getting more collateral financial support. In the mission toward converting activity groups into business, SAF provided additional fund on a short term basis which included revolving fund, technology fund and shift to business. The study assessed the impact of these funds in augmenting the performance of over 600 activity groups in Kerala. The results showed that both sale turnover and income increased consequent to receipt of additional fund. The repayment rates were also high at 80 percent showing promising future.

Logic as Methodology

The article expresses the idea that the actual methodology is logic as a universal form, which is freely modified in accordance with the subject content of reality. Based on this principle, the socalled applied Sciences are criticized. This confirms the idea that method as logic and logic as a universal form of thinking adequately perform themselves only as an individual-personal ability within the subject-transforming activity. The principle of mind as the ability to Express the essence of a thing and form a concept is developed. The dialectical nature of this process and its opposite to the formal-empirical method are shown. The nature of consciousness is expressed through the problem of the relation of the universal and the special, and the logical form of judgment is expressed as its basis.

Not modern thoughts about education

The analysis of current philosophical and pedagogical approaches to educating students in the system of secondary and higher education is based on a number of publications in “Sea collection” for 1856–1860. It is noted, that one of the most important tasks of education in Russia is formation and strengthening of foundations of civil society. Offered is to focus efforts of educational institutions primarily on education of the person, formation of personality, capable of transforming activity that is imbued with ideals of serving the common good.

Sources Autonomy of the Subject of Social Relations

The paper explicates the ontological aspects of the Genesis of individuality in the social space, explains the nature of social activity in accordance with the degree of individualization of social construction. The author aims to explain the possibilities of indi-vidual social reflection and design of social partici-pation, contributing to the strengthening of society, the disclosure of their freedom through the knowledge of their own being as part of the univer-sal being. The paper uses the concept of the subject of social relations in a new way. The ontological basis of subjectivity is derived from the self-disclosure of all the properties of being in a particu-lar phenomenon, in a particular case, in the disclo-sure of the generic qualities of a person through reproducing and transforming activity. The study shows that self-knowledge and life in accordance with the constructed “I-image” as dialectics of knowledge about real and potentially sophisticated properties requires approbation in social creativity. The Genesis of individuality cannot be reduced only to the synthesis of social approval of “significant others” or the discovery of original ways of inclu-sion in the social space. The basis of individualiza-tion is the possibility of creative improvement of the life world on the basis of Autonomous decision-making, the discovery of significance for society and the world person himself as a being subject.

Intertextuality Theory and Translation

Intertextuality theory is one of the most complicated literary theories in contemporary literary criticism; it has inherent connections with translation. According to intertextuality theory, translation is a type of transforming activity intertextualized with language, text, culture and thinking, etc. Any translated text is a tissue in an immense network of complex, where the significance of each text unfolds through referring to each other. In some degree, intertextuality theory breaks the traditional idea of translation, and has great enlightenment on translation in many aspects.

Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.