HEALTHCARE： A COMPLEX SERVICE SYSTEM

Healthcare is indeed a complex service system, one requiring the technobiology approach of systems engineering to underpin its development as an integrated and adaptive system. In general, healthcare services are carried out with knowledge-intensive agents or components which work together as providers and consumers to create or co-produce value. Indeed, the engineering design of a healthcare system must recognize the fact that it is actually a complex integration of human-centered activities that is increasingly dependent on information technology and knowledge. Like any service system, healthcare can be considered to be a combination or recombination of three essential components — people (characterized by behaviors, values, knowledge, etc.), processes (characterized by collaboration, customization, etc.) and products (characterized by software, hardware, infrastructures, etc.). Thus, a healthcare system is an integrated and adaptive set of people, processes and products. It is, in essence, a system of systems which objectives are to enhance its efficiency (leading to greater interdependency) and effectiveness (leading to improved health). Integration occurs over the physical, temporal, organizational and functional dimensions, while adaptation occurs over the monitoring, feedback, cybernetic and learning dimensions. In sum, such service systems as healthcare are indeed complex, especially due to the uncertainties associated with the human-centered aspects of these systems. Moreover, the system complexities can only be dealt with methods that enhance system integration and adaptation.     

A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease

Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.     

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.     

γ-射线血管内照射治疗计划系统的研制

介绍了研究开发的三维血管内照射治疗计划系统，该治疗计划系统建立在三维医学图像和临床上常用的γ－射线源基础之上，集成了放射源剂量学数据管理，三维图像处理，治疗计划设计、剂量分布计算与显示、治疗计划评估和打印输出等功能模块，为了验证治疗计划的有效性，文中给出了2组实验数据，一组是与GammaMed治疗计划系统的对比结果，另一组是对实际弯曲血管的计划结果。     

An Optimal Algorithm To Recognize Robinsonian Dissimilarities

A dissimilarity D on a finite set S is said to be Robinsonian if S can be totally ordered in such a way that, for every i < j < k, D (i, j) ≤ D (i, k) and D (j, k) ≤ D (i, k). Intuitively, D is Robinsonian if S can be represented by points on a line. Recognizing Robinsonian dissimilarities has many applications in seriation and classification. In this paper, we present an optimal O (n ²) algorithm to recognize Robinsonian dissimilarities, where n is the cardinal of S. Our result improves the already known algorithms.     

Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development

Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that acts in developing and adult tissues. The Cyp26a1 (cytochrome p450, 26) protein metabolizes retinoic acid into more polar hydroxylated and oxidized derivatives. Whether some of these derivatives are biologically active metabolites has been debated. Cyp26a1(-/-) mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development. This hypothesis suggests that the Cyp26a1(-/-) phenotype could be rescued under conditions in which embryonic retinoic acid levels are decreased. We show that Cyp26a1(-/-) mice are phenotypically rescued by heterozygous disruption of Aldh1a2 (also known as Raldh2), which encodes a retinaldehyde dehydrogenase responsible for the synthesis of retinoic acid during early embryonic development. Aldh1a2 haploinsufficiency prevents the appearance of spina bifida and rescues the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1(-/-) mice. Thus, some of these double-mutant mice can reach adulthood. This study is the first report of a mutation acting as a dominant suppressor of a lethal morphogenetic mutation in mammals. We provide genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida.     

Human DNA ligase I completely encircles and partially unwinds nicked DNA

The end-joining reaction catalysed by DNA ligases is required by all organisms and serves as the ultimate step of DNA replication, repair and recombination processes. One of three well characterized mammalian DNA ligases, DNA ligase I, joins Okazaki fragments during DNA replication. Here we report the crystal structure of human DNA ligase I (residues 233 to 919) in complex with a nicked, 5' adenylated DNA intermediate. The structure shows that the enzyme redirects the path of the double helix to expose the nick termini for the strand-joining reaction. It also reveals a unique feature of mammalian ligases: a DNA-binding domain that allows ligase I to encircle its DNA substrate, stabilizes the DNA in a distorted structure, and positions the catalytic core on the nick. Similarities in the toroidal shape and dimensions of DNA ligase I and the proliferating cell nuclear antigen sliding clamp are suggestive of an extensive protein-protein interface that may coordinate the joining of Okazaki fragments.     

Genome evolution in yeasts

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.