Business Process Re-engineering in Practice—An Example of A Medium-Sized Slovenian Company in Difficulties

Among the contemporary and globally adopted management methods, Business Process Re-engineering (BPR) is the most influential one. Although it was developed in American social and economic environment, it has been widely practiced also in Europe. Experience has demonstrated though that uncritical application of the original American BPR substance to European entrepreneurial practice is as a rule inefficient, often even incompatible with the basic social values. The globally adopted BPR method of company re-engineering is aimed at an increase in competitiveness and must be specified expertly and in view of its substance or adapted to numerous social and economic factors, i.e., requisitely holistically. This article deals with the application of the BPR method in the case of a medium-sized Slovenian company in difficulties. It illustrates the criteria for the selection of a management method of an innovative business change management that is the most efficacious in the Slovenian economy. The BPR project realization is defined from the viewpoint of the given implementation projects and criteria, enabling continual evaluation of the attained results of company reorganization. It presents a good case of informal systemic, i.e., requisitely holistic thinking and action.     

Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B

Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.     

Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.     

Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.     

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia

Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin?2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin?2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin?2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin?2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.