Structure and Dynamics of Sheep Systems in Bosnia and Herzegovina

The paper presents the analysis of dynamics and structure of the sheep systems in Bosnia and Herzegovina assuming that they suffered a decrease of animal and farms consistency in the last 6 decades. Since 1991 neither a general nor agricultural censuses were made to provide information about the present state of sheep farming in the country. An analysis of the available statistical records of agricultural trends related to the sheep sector was performed. In addition, a depth questionnaire by consulting national experts was performed in order to obtain relevant information on the spatial distribution, consistency, feeding management, production and environmental impact on the present structure of sheep production systems. A decrease in sheep number was observed over the last six decades, but less than in other species. Six main sheep systems in three biogeographical regions were identified. Differences in animal spatial distribution, production purpose and other characteristics of the systems indicate that the environmental and socio-economic factors throughout the country strongly influence the choice of breeding methods and management. All consulted experts indicated the lack of support for sheep systems in relation to agro environmental management, landscape conservation and biodiversity preservation

Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis Against Enterotoxigenic Escherichia coli Infection

Background. Enterotoxigenic Escherichia coli (ETEC) cause diarrheal illness in infants in the developing world and travelers to endemic countries including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea. Methods. Mice transgenic for human immunoglobulin genes were immunized with CfaE to generate a panel of human monoclonal IgG1 antibodies (HuMAbs). The most potent IgG1 identified in the in vitro functional assays were selected and isotype switched to secretory IgA (sIgA) and tested in animal colonization assays via oral administration. Results. Over 300 unique anti-CfaE IgG1 HuMabs were identified. The lead IgG1 anti-CfaE HuMAbs completely inhibited hemagglutination and blocked adhesion of ETEC to Caco-2 cells. Epitope mapping studies revealed that HuMAbs recognized epitopes in the N-terminal domain of CfaE near the putative receptor binding site. Oral administration of anti-CfaE antibodies in either IgG or secretory IgA isotypes inhibited intestinal colonization in mice challenged with ETEC. A two to four log decrease of colony forming units was observed as compared to irrelevant isotype controls. Conclusions. We identified fully human monoclonal antibodies against CfaE adhesion domain that can be potentially employed as an immunoprophylaxis to prevent ETEC-related diarrhea

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation

Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis

Proteomics in antitumor research

Proteins are the molecular players of fine-tuned regulatory pathways that underlie the behavior of any cell type. Derangement of this wide protein circuitry has a profound effect on cell life and ultimately contributes to the development of diseases such as cancer. New proteomic technologies are rapidly evolving to define and characterize the nodes of this altered protein network, both inside and outside cancer cells. Hopefully, these technologies will become user-friendly laboratory tools to improve cancer management from early detection to the development of rational and patienttailored therapeutic strategies

Casting light on molecular events underlying anti-cancer drug treatment: what can be seen from the proteomics point of view?

Regardless of continuous advances in technology and expansion of the knowledge in the field of genomic information, cancer still remains one of the leading causes of death in developed countries for many reasons, including non-selectiveness of commonly used anti-cancer drugs that often influence non-specific rather than tumour-specific targets. As cancer cells are characterized by the ability to divide and multiply in an uncontrolled manner whereby a set of specific proteins modulate cell division processes, proteomics seems to be a suitable tool for seeking out molecular mediators of anti-cancer drugs action and resistance, thus improving chemotherapy outcome. This review will focus on the recent knowledge of the molecular mechanisms involved in the anti-cancer drugs response revealed by the proteomics tools. In addition, we will touch upon the effects of "gene drugs" with p53 and p21(waf1/cip1) genes on the protein complement of tumour cells assessed by the two-dimensional gel electrophoresis combined with mass spectrometry. Such studies could substantially contribute to further drug optimization prior to its clinical use and represent an important but still small step in the long way of drug discovery. However, fluctuations in protein expression, distribution, posttranslational modifications, interactions, functions and compartmentalization make it difficult to use exclusively expression proteomics data without putting it in broader biological context. Thus, the challenge today is to shift from the identification of drug response and disease biomarkers to more time-consuming process of revealing the biochemical mechanism that connects a specific protein with a disease or cellular response to a drug

Functional genomics in identification of drug targets in Dupuytren's contracture

Although functional genomics methods offer new viewpoint on molecular processes involved in particular pathological state, these methods, in particular proteomics, are still under-represented in Dupuytren's contracture research. However, several recent papers based on functional genomics technologies represent a breakthrough in studying Dupuytren's contracture as they revealed new molecular players that had been impossible to detect by traditional molecular biology methods. Using computational tools to provide biological context for such broad arrays of data accelerates the process of homing in on the potential molecular markers and drug targets. Interactomes, maps of protein-protein interactions characteristic for the disease and as such putative models of its molecular pathology, are especially useful for this purpose, facilitating the transition from global screening methods to specific experiments aimed at therapy development. The combination of these approaches in Dupuytren's contracture research might therefore facilitate the discovery of novel therapeutic targets and diagnostic markers indicative of disease progression