Human Linkage Research Articles

HEAVEN: The head anastomosis venture Project outline for the first human head transplantation with spinal linkage (GEMINI)

In 1970, the first cephalosomatic linkage was achieved in the monkey. However, the technology did not exist for reconnecting the spinal cord, and this line of research was no longer pursued. In this paper, an outline for the first total cephalic exchange in man is provided and spinal reconnection is described. The use of fusogens, special membrane-fusion substances, is discussed in view of the first human cord linkage. Several human diseases without cure might benefit from the procedure.

Multi-species data integration and gene ranking enrich significant results in an alcoholism genome-wide association study

BackgroundA variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation.ResultsIn this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism.ConclusionsThese results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.

Human resource management and total quality management linkage – rhetoric and reality

PurposeThe purpose of this paper is to investigate the impact of human resource management (HRM) practices on the implementation of total quality management (TQM) practices, on the one hand, and to investigate the impacts of HRM and TQM practices on the organizational quality performance, on the other.Design/methodology/approachData were collected through a survey designed to be answered by human resource managers and quality managers. Data were analyzed by means of descriptive statistics and correlation analysis.FindingsHRM practices such as training and development, employee career planning, and recruiting and selection had the greatest significant influences on the implementation of TQM. The results of the study also reveal that HRM practices and TQM practices have a significant effect on organizational quality performance, especially employee quality awareness, customer satisfaction, and company image.Research limitations/implicationsThe sample of the study was not large enough to permit the use of any sophisticated statistical analysis. Further research should be considered in order to gather more information about HRM and TQM linkages in different business industries.Practical implicationsThe HRM system and TQM system should be aligned with corporate strategy to ensure that HRM and TQM practices are in congruence with each other. Also, there should be evidence of existence of an integrated system for assessing the success of these practices.Originality/valueThe paper offers insights into the linkage between HRM and TQM practices, focusing on Jordan. Therefore, this paper offers some useful suggestions that may lead to translating quality rhetoric into concrete business practice.

Charcot–Marie–Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype – Usefulness of human mapping chip linkage analysis in a Czech family

Charcot–Marie–Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 – missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient’s healthy father.

Technological Change from Foreign Firms: Firm-Level Case Studies in the Kenyan Context

Foreign direct investment and technological spillovers are among the most widely studied to understand their role in learning, capability building and innovation management. The purpose of this paper is to examine the role of FDI in industrial development in the sub Saharan region but using an alternative framework taking Kenya as a case study country. Specifically, the paper investigates whether presence of FDI in manufacturing industry stimulates spillover occurrence. This is done following a unique analytical framework developed taking into consideration human resource development, linkages, competition and demonstration effects. On the basis of this framework, foreign presence stimulated spillover occurrence in Kenya’s industry. There was tremendous evidence of learning, capability building and innovation due to spillover occurrence. The main limitation of this paper is that results obtained cannot be generalized since the five foreign firms studied cannot be considered comprehensive representatives of the entire manufacturing industry. The results need to change our thinking with regard to policy pertaining to the role FDI plays in a host country’s industrial development. This paper presents the only known work based in Africa focusing on FDI, spillovers, learning, capability building and innovation. The case studies, though ambitious, present findings which need to change our thinking about the past results and methodologies of the past studies on FDI and spillovers.

Exome and whole-genome sequencing for gene discovery: The future is now!

Exome and whole-genome sequencing for gene discovery: The future is now!

Cashing In Across the Golden Triangle: Thailand's Northern Border Trade with China, Laos, and Myanmar.

DOI: 10.1355/ae29-2fCashing In Across the Golden Triangle: Thailand's Northern Border Trade with China, Laos, and Myanmar. By Thein Swe and Paul Chambers. Chiang Mai, Thailand: Mekong Press, 2011. Pp.xx, 212.The book tells the story of how an emerging fourcountry, cross-border natural economic territory transformed the Golden Triangle, once no more than a lawless drug trafficking frontier into an example of flourishing regional economic cooperation. Natural refers to the mosaic of vertically and horizontally integrated markets that cross national borders within the territory. The volume that analyses this transformation is the result of a confluence involving a first-rate publisher and two quality co-authors. Mekong Press was initiated in 2005 by Silkworm Books with financial support from the Rockefeller Foundation. Silkworm is a publisher of note when it comes to socioeconomic, political and cultural issues centring on the northern regions of Thailand and the crossborders to which they connect. Co-authors Thein Swe and Paul Chambers occupy faculty positions at the South East Asian Institute of Global Studies at Chiang Mai's Payap University.From the outset the co-authors write with the realization that many of their readers have a limited understanding of the region's geography, economic and political structures well the production, finance, trade and human migration patterns and linkages that continue to form. They write both to this audience and to other readers who are well informed about the enormous regional changes that are taking place - including the costs and benefits to which they give rise.The book's early chapters focus on the substantive nature of the transformation, particularly in Northern Thailand which plays a major role in the development of new patterns of production, distribution, labour migration, tourism, border trade and finance. They point out that tourism is in the process of becoming an ever more prominent economic sector. In support of these activities new and rejuvenated infrastructure facilities are being put into place in transportation (including roads, bridges and rail transportation), communication (namely land-based and wireless phones) and energy availability including from fourteen Chinese hydropower dams constructed and operating along the Upper Mekong.As patterns of cross-border trade in goods and services continue to evolve they lead to transport corridors that in turn facilitate the growth of retail and wholesale establishments located along the way; that is, transport corridors both facilitate and generate economic activity. This helps cities to grow, and the Northern Thailand town of Mae Sai is a good example of this aspect of the region's dynamism. It is a town of 60,000 that now boasts an array of retailers and wholesalers, a nearby casino complex to attract visitors and it is a strategic border crossing point into Myanmar. The Asian Highway Network works its way through Mae Sai on its way to other market towns within the economic territory.It is a burgeoning and exciting place and Swe and Chambers capture this phenomenon vividly. Not only do they analyse the positive aspects of the territories' economic expansion (for example, in terms of productivity, production, employment and income generation) but they also analyse some of the problems that have arisen. For example, there are strategic and reliability issues due to distances between facilities leading to transportation constraints. Equitable water access and energy sharing remain a political challenge. The hydro power dams on the Upper Mekong as well increasingly longer dry seasons have caused a decrease in Mekong water levels, making river commerce more difficult (p. 104). In addition, growth based upon the cashing in process is uneven with some residents of the region left behind, including cross-border migrants many of whom settled in the Chiang Mai/Chiang Rai/Mae Sai part of Northern Thailand. …

The unexpected always happens.

The unexpected always happens.

Linkages to Public Land Framework: toward embedding humans in ecosystem analyses by using “inside-out social assessment”

This article presents the ''Linkages to Public Land'' (LPL) Framework, a general but comprehensive data-gathering and analysis approach aimed at informing citizen and agency decision making about the social environment of public land. This social assessment and planning approach identifies and categorizes various types of linkages that people have to public land and guides the tasks of finding and using information on people in those linkages. Linkages are defined as the ''coupling mechanisms'' that explain how and why humans interact with ecosystems, while linkage analyses are empirical investigations contextualized both temporally and geographically. The conceptual, legal, and theoretical underpinnings of five basic linkage categories (tribal, use, interest, neighboring land, and decision making) and further refinement into subcategories are explained. These categories are based upon the complex property and decision-making regimes governing public land. Applying an ''inside-out'' analytic perspective, the LPL Framework assesses the social environment inside public land units and traces linkages out into the larger social environment, instead of assessing the outside social environment (communities or stakeholders) and assuming linkages exist between the social entities and public lands, as is generally done in social assessments. The LPL Framework can be utilized in management activities such as assessing baseline conditions and designing monitoring protocols, planning and evaluating management alternatives, analyzing impacts of decisions, structuring public involvement and conflict management efforts, and conducting collaborative learning and stewardship activities. The framework enhances understanding of human dimensions of ecosystem management by providing a conceptual map of human linkages to public land and a stepwise process for focusing and contextualizing social analyses. The framework facilitates analysis of the compatibilities, conflicts, and trade-offs between various linkages, and between cumulative human linkages and capabilities of public land to sustain them. While the LPL Framework was developed for use in planning for U.S. National Forests, it could be applied to other types of public land in the United States and adapted and extended to public lands and common property areas in other countries.

Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology.

Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.

Environmental change, pathogens, and human linkages. Part 2: concepts and perspectives

Environmental change, pathogens, and human linkages. Part 2: concepts and perspectives

The Arrestin Domain-Containing 3 Protein Regulates Body Mass and Energy Expenditure

A human genome-wide linkage scan for obesity identified a linkage peak on chromosome 5q13-15. Positional cloning revealed an association of a rare haplotype to high body-mass index (BMI) in males but notfemales. The risk locus contains a single gene, "arrestin domain-containing 3" (ARRDC3), an uncharacterized α-arrestin. Inactivating Arrdc3 in mice led to a striking resistance to obesity, with greater impact on male mice. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure through increased activity levels and increased thermogenesis of both brown and white adipose tissues. ARRDC3 interacted directly with β-adrenergic receptors, and loss of ARRDC3 increased the response to β-adrenergic stimulation in isolated adipose tissue. These results demonstrate that ARRDC3 is a gender-sensitive regulator of obesity and energy expenditure and reveala surprising diversity for arrestin family protein functions.

Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African–Americans

Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African-Americans. We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African-Americans and performed a case-control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components). A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10) and rs4657251 in the RGS5 gene (P = 9.7 × 10) were the top hits. Effect size for each of these variants was approximately 2-3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01). These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.

Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

Prioritization and Association Analysis of Murine-Derived Candidate Genes in Anxiety-Spectrum Disorders

Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.

Environmental change, pathogens, and human linkages. Part 1: ecological case studies

Environmental change, pathogens, and human linkages. Part 1: ecological case studies

Molecular and developmental mechanisms of congenital heart valve disease

Congenital heart disease occurs in approximately 1% of all live births and includes structural abnormalities of the heart valves. However, this statistic underestimates congenital valve lesions, such as bicuspic aortic valve (BAV) and mitral valve prolapse (MVP), that typically become apparent later in life as progressive valve dysfunction and disease. At present, the standard treatment for valve disease is replacement, and approximately 95,000 surgical procedures are performed each year in the United States. The most common forms of congenital valve disease include abnormal valve cusp morphogenesis, as in the case of BAV, or defects in extracellular matrix (ECM) organization and homeostasis, as occurs in MVP. The etiology of these common valve diseases is largely unknown. However, the study of murine and avian model systems, along with human genetic linkage studies, have led to the identification of genes and regulatory processes that contribute to valve structural malformations and disease. This review focuses on the current understanding and therapeutic implications of molecular regulatory pathways that control valve development and contribute to valve disease.

Site-Specific Modification of Recombinant Proteins: A Novel Platform for Modifying Glycoproteins Expressed in E. coli

The site-specific modification of proteins is expected to be an important capability for the synthesis of bioconjugates in the future. However, the traditional repertoire of reactions available for the direct modification of proteins suffers from lack of specificity, necessitating costly downstream processing to isolate the specific species of interest. (1) Here, we use a well-established, glycan-specific chemistry to PEGylate model glycoproteins, each containing a unique reactive GalNAc attached to a specifically engineered threonine residue. By engineering E. coli to execute the initial steps of human, mucin-type O-glycosylation, we were able to obtain homogeneous site-specifically modified glycoproteins with fully human glycan linkages. Two mucin-based reporters as well as several fusion proteins containing eight-amino-acid GalNAc-T recognition sequences were glycosylated in this engineered glycocompetent strain of E. coli. The use of one sequence in particular, PPPTSGPT, resulted in site-specific glycan occupancy of approximately 69% at the engineered threonine. The GalNAc present on the purified glycoprotein was oxidized by galactose oxidase and then coupled to hydroxylamine functionalized 20 kDa PEG in the presence of aniline. The glycoprotein could be converted to the PEGylated product at approximately 85% yield and >98% purity as determined by comparison to the products of control reactions.

A Genome-Wide Linkage Analysis in 181 German Sarcoidosis Families Using Clustered Biallelic Markers

Sarcoidosis (SA) is a systemic granulomatous inflammatory disorder with complex etiology and strong clustering in families. Genome-wide association studies have been successful in the identification of common risk variants for the disease. To reveal susceptibility variants with low frequencies but strong effects, we performed a genome-wide linkage scan in a large sample of SA families. We genotyped 528 members of 181 German SA families for 3,882 single nucleotide polymorphism assays from the SNPlex System Human Linkage Mapping Set 4K. Nonparametric linkage analysis revealed one region of suggestive linkage on chromosome 12p13.31 at 20 cM (logarithm of odds [LOD] = 2.53; local P value = .0003) and another linkage peak of nearly suggestive linkage on 9q33.1 at 134 cM (LOD = 2.12; local P value = .0009). The latter has been reported to show suggestive evidence for linkage in a sample of 229 African American SA families previously. Analysis of acute and chronically affected families revealed a subphenotype-specific linkage pattern and an additional, nearly suggestive linkage peak on chromosome 16p13.11 at 38 cM (LOD = 2.09; local P value = .001), which was confined to acute SA. Our results propose that the respective regions might harbor yet-unidentified, possibly subphenotype-specific risk factors for the disease (eg, with immune-related functions like the tumor necrosis factor receptor 1). They should be proved to be important for SA pathogenesis and investigated in detail with an emphasis on rare variants. Subphenotype-specific risk factors might serve for prognosis of the clinical course of the disease.

Compulsivity in mouse strains homologous with chromosomes 7p and 15q linked to obsessive‐compulsive disorder

Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by obsessions and compulsions. The core symptom of OCD is compulsivity, the inability to stop thinking or acting when you want to, despite being aware of the uselessness of the content or the adverse consequences. To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, a panel of chromosome substitution (CS) strains, derived from mice that suppress (C57BL/6J strain) or maintain (A/J strain) high levels of repetitive wheel running during 2 hr of daily limited food access, was screened for this compulsive behavior. Following the genetic screen, we found linkage between compulsive wheel running and mouse chromosomes 2, 6, and 7 that show overlap with recently identified human linkage regions for OCD on chromosomes 7p and 15q. In the overlapping (human/mouse) genomic region, the CRH receptor 2 (CRHR2) gene was tested in a human case-control study. An initial exploration in OCD cases versus controls failed to detect an association between four-candidate CRH2R SNP's within this homologous linkage region and OCD. Genetic fine mapping of compulsivity in mice provides new opportunities to reveal mechanisms underlying this significant psychiatric trait.