Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis

BACKGROUND AND AIMS Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options

The Current State of Performance Appraisal Research and Practice: Concerns, Directions, and Implications

On the surface, it is not readily apparent how some performance appraisal research issues inform performance appraisal practice. Because performance appraisal is an applied topic, it is useful to periodically consider the current state of performance research and its relation to performance appraisal practice. This review examines the performance appraisal literature published in both academic and practitioner outlets between 1985 and 1990, briefly discusses the current state of performance appraisal practice, highlights the juxtaposition of research and practice, and suggests directions for further research

Magnetostimulated Chandges of Microhardness in Potassium Acid Phthalate Crystals

A decrease in microhardness along the (010) cleavage in potassium acid phthalate single crystals by 15--18% after the application of a permanent magnetic field was revealed for the first time. It is shown that the effect revealed is of the volume character. The role of interlayer water in the processes stimulated by a magnetic field is studied., Interlayer water plays does not cause the observed changes it only plays the part of an indicator of these changes in potassium acid phthalate crystals in a magnetic field. It is established that microhardness in the (100) plane of the crystal in an applied a magnetic field first increases by 12--15% and then remains constant in time within the accuracy of the experiment. The possibility of varying the crystal structure of potassium acid phthalate crystals by applying magnetic fields inducing rearrangement in the system of hydrogen bonds or in the defect structure is discussed.Comment: 6 pages, 7 figure

Financing Higher Education in Sub-Saharan Africa: A Proposed Model Based on the Experiences of Ugandan Higher Education Institutions and Exemplary Practices from the Asian Tigers

Financing higher education has become one of the most contentious educational issues in both developed and third world countries. Among the causes highlighted by researchers are changing fiscal policies and government resource allocation priorities, coupled with rapid increases in college-going populations. Today, there is an upsurge in the numbers of colleges and enrollments all over the world. This upsurge and the forces of globalization, which put demands on institutions in terms of international rankings and the need to adopt the latest technologies, are putting enormous fiscal pressure on higher education institutions and their funders. Increasing enrollments without sufficient funding lead to substandard facilities and a decline in academic standards. To close that funding gap, institutions have resorted to privatization, which includes (inter alia) tuition charges and other fees. This has effectively turned the traditional model of higher education upside down. The challenge is: How do universities ensure they admit only the most qualified students and provide them with the best instruction, using state-of-the-art facilities, in a learning system run by highly qualified and motivated faculty staff? Against that background, this chapter analyzes best practices for financing higher education in developing countries that have vibrant higher education sectors (such as Malaysia), together with the challenges, practices, and experiences of funding Ugandan higher education institutions. The chapter ultimately suggests a suitable framework for higher education financing in Uganda and similar sub-Saharan African countries

Protist-Type Lysozymes of the Nematode Caenorhabditis elegans Contribute to Resistance against Pathogenic Bacillus thuringiensis

Pathogens represent a universal threat to other living organisms. Most organisms express antimicrobial proteins and peptides, such as lysozymes, as a protection against these challenges. The nematode Caenorhabditis elegans harbours 15 phylogenetically diverse lysozyme genes, belonging to two distinct types, the protist- or Entamoeba-type (lys genes) and the invertebrate-type (ilys genes) lysozymes. In the present study we characterized the role of several protist-type lysozyme genes in defence against a nematocidal strain of the Gram-positive bacterium Bacillus thuringiensis. Based on microarray and subsequent qRT-PCR gene expression analysis, we identified protist-type lysozyme genes as one of the differentially transcribed gene classes after infection. A functional genetic analysis was performed for three of these genes, each belonging to a distinct evolutionary lineage within the protist-type lysozymes (lys-2, lys-5, and lys-7). Their knock-out led to decreased pathogen resistance in all three cases, while an increase in resistance was observed when two out of three tested genes were overexpressed in transgenic lines (lys-5, lys-7, but not lys-2). We conclude that the lysozyme genes lys-5, lys-7, and possibly lys-2 contribute to resistance against B. thuringiensis, thus highlighting the particular role of lysozymes in the nematode's defence against pathogens