Grzegorz Wegrzyn – författare

Mucopolysaccharidoses (MPS) are caused by a deficiency of lysosomal enzyme activities needed to degrade glycosaminoglycans (GAGs), which are long unbranched polysaccharides consisting of repeating disaccharides. GAGs include: Chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in combination depending on the specific enzyme deficiency. There are eleven known enzyme deficiencies, resulting in seven distinct forms of MPS with a collective incidence higher than 1 in 25,000 live births. Accumulation of undegraded metabolites in lysosomes gives rise to distinct clinical syndromes. Generally, the clinical conditions progress if untreated, leading to developmental delay, systemic skeletal deformities, and early death.Other clinical features include coarse facial features, corneal clouding, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, heart valvular disease and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis. Patients may need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy throughout their lifetime. Current measures to intervene in bone disease progression and CNS involvement are not perfect and palliative, and improved therapies are urgently required and are being proposed.Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzymes to the brain and bones, especially avascular cartilage, to prevent or ameliorate the devastating neurological defects and skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion and damage, since the severity of CNS involvement and skeletal dysplasia is associated with the level of activity in a patient's daily life.For the maximum benefit of available therapies, early detection and intervention are critical. Newborn screening and diagnostic systems have been developed by using tandem mass spectrometry. We review the history of diagnosis and newborn screening as well. Overall, this book illustrates a to-date overview of the pathogenesis, diagnosis, biomarkers, screening, and updated therapies as well as their impact on MPS, including ERT, HSCT, gene therapy, and anti-inflammatory drugs. History and activities of MPS societies are also described. It is a comprehensive textbook meant to cover many areas in the field of MPS and appeals to a broad spectrum of readers including physicians, scientists, students, pharmaceutical companies, and MPS communities.

This work describes the current knowledge of biochemical mechanisms regulating initiation of DNA replication in Escherichia coli, which focuses on the control of  activity of the DnaA protein. Examples of direct linkages between DNA replication and other cellular processes are provided. In addition, similarities of the mechanisms of regulation of DNA replication operating in prokaryotic and eukaryotic cells are identified, and implications for understanding more complex processes, like carcinogenesis are suggested.Studies of recent years provided evidence that regulation of DNA replication in bacteria is more complex than previously anticipated. Multiple layers of control seem to ensure coordination of this process with the increase of cellular mass and the division cycle. Metabolic processes and membrane composition may serve as points where integration of genome replication with growth conditions occurs. It is also likely that coupling of  DNA synthesis with cellular metabolism may involve interactions of replication proteins with other macromolecular complexes, responsible for various cellular processes. Thus, the exact set of factors participating in triggering the replication initiation may differ depending on growth conditions. Therefore, understanding the regulation of DNA duplication requires placing this process in the context of the current knowledge on bacterial metabolism, as well as cellular and chromosomal structure. Moreover, in both Escherichia coli and eukaryotic cells, replication initiator proteins were shown to play other roles in addition to driving the assembly of replication complexes, which constitutes another, yet not sufficiently understood, layer of coordinating DNA replication with the cellcycle.