Alternative Linkage Research Articles

A Statistically Valid Alternative to the TDT

Objective: To present an alternative linkage test to the transmission/disequilibrium test (TDT) which is conservative under the null hypothesis and generally more powerful under alternatives. Methods: The exact distribution of the TDT is examined under both the null hypothesis and relevant alternatives. The TDT is rewritten in an alternate form based on the contributions from each of the three relevant parental mating types. This makes it possible to show that a particular term in the estimate is an exact tie and thus to rewrite the estimate without this term and to replace the multinomial ‘variance estimate’ of Spielman et al. [Am J Hum Genet 1993;52:506–516] by the binomial variance. Results: The resulting test is shown to be a stratified McNemar test (SMN). The significance level attained by the SMN is shown to be conservative when compared to the asymptotic χ² distribution, while the TDT often exceeds the nominal level α. Under alternatives, the proposed test is shown to be typically more powerful than the TDT. Conclusion: The properties of the TDT as a statistical test have never been fully investigated. The proposed test replaces the heuristically motivated TDT by a formally derived test, which is also computationally simple.

Beyond agri-environmental policy: towards an alternative model of rural environmental governance

Following the Second World War there were clear priorities for the domestic production of food. Agriculture was viewed as playing a central role in the protection of the rural environment and the support of the rural economy. These assumptions have now been largely rejected and a new framework for the conservation of the countryside is needed. The development of agri-environmental policy signals a start, but there are a number of limitations to this approach. A wider framework is required that includes a variety of alternative linkage mechanisms between the demand for countryside goods and the control of land. These include a range of alternative institutional arrangements among individuals and organisations, with significant roles for government, market and non-profit organisations. No single model can deliver the variety of environmental characteristics that is sought. The development of this new framework presents a challenge for the governance of the countryside.

Molecular strategies for fimbrial expression and assembly.

Fimbriae or pili are long, filamentous, multimeric macromolecules found on the bacterial cell surface. Bacteria express a diverse array of fimbriae or pili that are involved in bacterial adherence and invasion. Fimbriae can be categorized based on their modes of expression and assembly. Type I fimbriae and P pili are distributed peritrichously and translocated to the cell surface by a chaperone/usher pathway. Type 4 pili are located at the pole of the cell and assembled via the type II secretion system. Curli fimbriae are coiled surface structures assembled by an extracellular nucleation/precipitation pathway. Fimbriae of oral gram-negative and gram-positive bacteria have not been well-studied as compared with the fimbriae of enteric pathogens. Oral pathogens, such as Eikenella corrodens, Actinobacillus actinomycetemcomitans, and Porphyromonas gingivalis, possess fimbriae that have been implicated in bacterial adhesion and invasion. These fimbriae are potential virulence factors in oral infectious processes. A. actinomycetemcomitans and E. corrodens have Type 4-like fimbriae, whereas P. gingivalis displays a unique type of fimbriae. To date, fimbriae of the oral primary colonizers, Actinomyces naeslundii and Streptococcus parasanguis, represent the only fimbriae characterized for any gram-positive bacteria. The putative major fimbrial subunits, FimA and FimP of A. naeslundii and Fap1 of S. parasanguis, contain a signal sequence and cell-wall-sorting signal. The presence of extensive dipeptide repeats in Fap1 makes it unique among fimbrial molecules. Based on experimental data, a nucleation/precipitation pathway is proposed for fimbrial biogenesis of both S. parasanguis and A. naeslundii, although we cannot rule out an alternative covalent linkage model. The model systems described in this review served as a framework for hypotheses for how the known molecular factors of fimbriae on oral bacteria may be expressed and assembled.

A new nonparametric linkage statistic for mapping both qualitative and quantitative trait loci.

We describe an alternative nonparametric linkage (NPL) statistic to that of Kruglyak et al. [Am. J. Hum. Genet. 58:1347-63, 1996] that can be used with qualitative phenotypes, and is easily extended for use with quantitative phenotypes. We analyzed the Genetic Analysis Workshop 12 simulated isolated population data, replicate 1, using two phenotypes; affected status (AFF) a dichotomous phenotype and quantitative trait Q5, which was chosen since it was the most strongly associated with AFF. One false positive significant NPL score was observed for the AFF phenotype. For Q5 a single region on chromosome 1 reached genome-wide significance. The peak of this signal was for marker D01G137 at 135.1 cM with a quantitative trait locus (QTL)-NPL score of 4.19. The nearest marker to the true location of the major gene (MG5 at 137.1 cM) was D01G139 at position 135.8 cM, where the QTL-NPL score was still high at 4.08.

Modelling feasibility of genetic approaches to human stroke

33 Background Twin, population and animal studies suggest that genetic factors are important in stroke. To date all research in humans has used case control (CC) methods to determine association between candidate genes and stroke. Alternative approaches include linkage analysis with the advantage of allowing detection of novel genes and transmission disequilibrium testing, which uses internal family controls e.g.parents(TDT) or unaffected sibs (S-TDT)to reduce the risk of population stratification which is a problem in case control studies. Despite theoretical benefits, the feasiblity of these methods remains unknown. Methods Family history was prospectively determined in 727 consecutive cerebrovascular patients and 623 age matched controls. Patients with suspected Mendelian syndromes were excluded. Parent and sibling status (alive or dead and the presence of stroke)was documented. The data was used to model the number of stroke patients required for the different study designs. Results Family history of young stroke (≤65)was an independent risk factor for ischaemic stroke OR 1.45 (95% CI 1.01–2.09) p=0.05, early onset proband stroke (≤65) OR 2.22(1.42–3.50)p=0.0005 and stroke due to large vessel disease OR 1.75 (1.09–2.83) p=0.02. In the age group Conclusion This study supports the role of independent genetic risk factors in stroke which have greater influence in young individuals. Novel approaches are potentially feasible, although linkage studies and TDT would require large scale multicentre collaborations.

Linkages between Citizens and Politicians in Democratic Polities

Research on democratic party competition in the formal spatial tradition of Downs and the comparative-historical tradition of Lipset and Rokkan assumes that linkages of accountability and responsiveness between voters and political elites work through politicians’ programmatic appeals and policy achievements. This ignores, however, alternative voter-elite linkages through the personal charisma of political leaders and, more important, selective material incentives in networks of direct exchange (clientelism). In light of the diversity of linkage mechanisms appearing in new democracies and changing linkages in established democracies, this article explores theories of linkage choice. It first develops conceptual definitions of charismatic, clientelist, and programmatic linkages between politicians and electoral constituencies. It then asks whether politicians face a trade-off or mutual reinforcement in employing linkage mechanisms. The core section of the article details developmentalist, statist, institutional, political-economic, and cultural-ideological theories of citizen-elite linkage formation in democracies, showing that none of the theories is fully encompassing. The final section considers empirical measurement problems in comparative research on linkage.

Vascular medicine: a natural subspecialty interest for the diabetologists

Diabetology has historically been twinned with the clinical discipline of endocrinology for obvious reasons: both concern conditions of hormone lack, resistance or excess. Such linkage has doubtless been of value to clinicians and their patients alike but an alternative or complementary linkage is arguably even more relevant – vascular medicine. Diabetes mellitus (and indeed many endocrinological conditions, e.g. thyrotoxicosis, Cushing's disease and acromegaly), influence morbidity and mortality through their effects on the cardiovascular system. Indeed diabetes has been considered a vascular disease and the belated recognition that type 2 diabetes is not ‘mild diabetes’ but is synonymous with increased cardiovascular risk underlines the relevance of the discipline of vascular medicine to the practising diabetologist. Contemporary specialist diabetic care requires the consultant to be conversant with the determinants of vascular risk and their amelioration. It is no longer acceptable to attempt to put the glucose right and turn a blind eye to difficult hypertension or dyslipidaemia. Management of diabetic foot disease requires clear understanding of the indications for angiography, angioplasty and surgical vascular reconstruction and, if patients are to be best served, the capacity to engage in informed dialogue with the vascular surgeon or interventional radiologist. The optimal diabetes centre must be capable of lipid management, rigorous blood pressure control and exercise prescription as well as dealing with secondary prevention in patients who have already suffered a stroke, amputation or heart attack. To establish such a resource for a group of patients with the insulin resistance syndrome who happen to have an elevation of blood glucose as well, but not for those without, appears irrational. Some may shudder at the thought of a diabetes (and vascular) health centre accommodating even more patients but whether or not this is practicable depends upon the nature of specialist review in such centres. If the increasing trend towards ‘one off’ consultation with careful risk stratification and clarification of the management plan that primary care subsequently pursues is adopted, more patients can be seen. Relevant non-diabetic groups might include women with a past history of gestational diabetes, patients following myocardial infarction and newly diagnosed patients with intermittent claudication. What else does the vascular physician do? The role varies from country to country and is to some extent dependent upon whether it is an accreditable speciality. The list is long and includes dealing with non-organ-specific vasculitides, vasospastic disorders, premature atherosclerosis and the unexplained swollen limb as well as providing a lead for that common, important yet Cinderella condition of venous thromboembolism. The growth in potent pharmacotherapy for reducing cardiovascular risk requires someone to take a local lead in this field, a role that cardiologists (with their increasingly interventional role) and vascular surgeons are too busy to assume. With the emergence of new treatments deriving from advances in vascular biology (e.g. therapeutic angiogenesis) new demands for the specialty will emerge. Vascular pathology is what converts diabetes from a condition to a disease. Vascular medicine is a fascinating speciality that is under-subscribed and needs individuals with the attributes and patient-centred approach of the diabetologist if the potential of modern therapy is to be realised.

The contribution of the O‐glycosylated protein Pir2p/Hsp150 to the construction of the yeast cell wall in wild‐type cells and β1,6‐glucan‐deficient mutants

The cell wall of yeast contains a major structural unit, consisting of a cell wall protein (CWP) attached via a glycosylphosphatidylinositol (GPI)-derived structure to beta 1,6-glucan, which is linked in turn to beta 1, 3-glucan. When isolated cells walls were digested with beta 1,6-glucanase, 16% of all CWPs remained insoluble, suggesting an alternative linkage between CWPs and structural cell wall components that does not involve beta 1,6-glucan. The beta 1,6-glucanase-resistant protein fraction contained the recently identified GPI-lacking, O-glycosylated Pir-CWPs, including Pir2p/Hsp150. Evidence is presented that Pir2p/Hsp150 is attached to beta 1,3-glucan through an alkali-sensitive linkage, without beta 1,6-glucan as an interconnecting moiety. In beta 1,6-glucan-deficient mutants, the beta 1,6-glucanase-resistant protein fraction increased from 16% to over 80%. This was accompanied by increased incorporation of Pir2p/Hsp150. It is argued that this is part of a more general compensatory mechanism in response to cell wall weakening caused by low levels of beta 1,6-glucan.

Assignment of biochemical functions to glycosyl transferase genes which are essential for biosynthesis of exopolysaccharides in Sphingomonas strain S88 and Rhizobium leguminosarum.

Glycosyl transferases which recognize identical substrates (nucleotide-sugars and lipid-linked carbohydrates) can substitute for one another in bacterial polysaccharide biosynthesis, even if the enzymes originate in different genera of bacteria. This substitution can be used to identify the substrate specificities of uncharacterized transferase genes. The spsK gene of Sphingomonas strain S88 and the pssDE genes of Rhizobium leguminosarum were identified as encoding glucuronosyl-(B1-->4)-glucosyl transferases based on reciprocal genetic complementation of mutations in the spsK gene and the pssDE genes by segments of cloned DNA and by the SpsK-dependent incorporation of radioactive glucose (Glc) and glucuronic acid (GlcA) into lipid-linked disaccharides in EDTA-permeabilized cells. By contrast, glycosyl transferases which form alternative sugar linkages to the same substrate caused inhibition of polysaccharide synthesis or were deleterious or lethal in a foreign host. The negative effects also suggested specific substrate requirements: we propose that spsL codes for a glucosyl-(beta1-->4)-glucuronosyl transferase in Sphingomonas and that pssC codes for a glucuronosyl-(beta1-->4)-glucuronosyl transferase in R. leguminosarum. Finally, the complementation results indicate the order of attachment of sphingan main-chain sugars to the C55-isoprenylphosphate carrier as -Glc-GlcA-Glc-isoprenylpyrophosphate.

Linking the health utilities index to National Medical Expenditure Survey data.

Measures of health-related quality of life (HR-QOL) are becoming increasingly important in assessing the effects of chronic illness and healthcare interventions designed to treat them. Obtaining measures of HR-QOL for a nationally representative sample of individuals would enhance understanding of health status in the US, and promote further study of the economic causes and effects of health status. This study reports on our efforts to link a prominent HR-QOL scale, the Health Utilities Index Mark I (HUI), to the National Medical Expenditure Survey (NMES). Six distinct algorithms were constructed for linking the HUI to NMES. These alternative linkage algorithms yielded HUI measures that were highly intercorrelated (p = 93 to 99%). Multivariate regression analyses performed to predict variations in HR-QOL revealed that the HUI exhibited good predictive validity--the HUI demonstrated lower quality of life for a variety of chronic illnesses, and wealthier individuals and better educated individuals had a higher quality of life. In contrast to some previous HR-QOL research, the present analysis demonstrates that: (i) cancer is negatively and significantly related to quality of life; and (ii) smoking is negatively and significantly related to quality of life. Overall, the results suggest that the HUI linkages to NMES provide reliable and valid measures of quality of life. As such, items from the NMES can be grouped and linked in such a way as to obtain health state utility values. These values should be of use to those who wish to understand the global health of the US population for policy-making efforts.

Parameter sensitivity of a mathematical model of the anterior cruciate ligament.

This paper presents the results of an investigation into parameter sensitivity of a mathematical model of the human anterior cruciate ligament (ACL). The model ACL comprised a continuous array of fibres mapped between part-elliptical attachment areas on the femur and tibia. Relative motion of the two bones was controlled by a planar four-bar linkage. Parameter modifications were: (a) an alternative set of values for the coordinates of the four-bar linkage joints; (b) rotation of the attachment areas of the ligament by +/- 30 degrees; and (c) variation of some mechanical properties. The alternative four-bar linkage parameter set produced extremely large changes in ACL force values, up to 130 per cent. Rotating the tibial attachment changed forces by less than 20 per cent, whereas rotating the femoral attachment changed forces by up to 100 per cent. Altering the mechanical parameters produced the smallest differences in force, under 15 per cent. These results highlight the importance, when using a theoretical model, of establishing the values of the parameters defining the model as accurately as possible and of carrying out a parameter sensitivity study. From a clinical viewpoint, they also suggest that, when reconstructing a ruptured ACL, one of the most important considerations must be to position the femoral attachment of the graft as accurately as is feasible.

DUAL BEHAVIOR OF ACETONITRILE IN A NEW CADMIUM CYANIDE CLATHRATE: CRYSTAL STRUCTURE OF Cd(CH3CN)2Cd(CN)4·2CH3CN

Abstract We report a new crystal structure of the title clathrate containing tetrahedral and octahedral Cd atoms in a ratio of 1:1. The preparation of the compound is similar to that of the cristobalite-like clathrate Cd(CN)2·G, where all Cd atoms are tetrahedral. The new inclusion compound crystallizes in the monoclinic space group C2/c, a = 12.337(4), b = 11.964(3), c = 13.594(3) A, β = 108.60(2)°, Z = 4, R = 0.034 for 1631 reflections. The three-dimensional host framework is built of alternate linkages between the tetrahedral Cd atom of the tetracyanocadmate and the octahedral Cd atom similar to that of the Hofmann-Td and the en-Td types. In the new clathrate dual behavior of acetonitrile, one as a unidentate ligand in the three-dimensional host framework and the other as the guest in the cage-like cavity, has been demonstrated.

External-internal linkages and overseas autonomy-control tension: the management dilemma of the Japanese R&D in Europe

By examining how external/internal linkages held by overseas R&D labs affect autonomy-control tension within multinational corporations (MNCs), managerial dilemmas pertinent to international R&D management are discussed, especially in the context of internationalization of Japanese R&D in Europe. R&D is liable to be affected by high autonomy-control tension due to countervailing institutional forces at the functional level (research/corporate) and the geographical level (host country/home country). The external linkages an overseas R&D lab develops tend to increase the expected degree of local autonomy vis-a-vis the parent. The external linkages tend to increase the need for internal control on the part of the parent, especially when such sensitive issues as intellectual property rights and research initiatives are involved. Managers use internal linkages as a condition based on which local autonomy can be granted. Similarly, a high degree of internal linkages tends to decrease the difficulty of internal control and would even allow for some potential increase in local autonomy. An alternative multinational linkage strategy becomes necessary for the Japanese MNCs in the era of global R&D management in which the conventional social/cultural control mechanism may break down. This paper attempts to provide a basic framework which enables the association of such differences in linkage patterns with autonomy-control tension in a systematic way so that some new insight would be obtained regarding this classic yet unresolved tension.

Stress Resistance in Saccharomyces cerevisiae Is Strongly Correlated with Assembly of a Novel Type of Multiubiquitin Chain

The covalent attachment of ubiquitin (Ub) to short-lived or damaged proteins is believed to be the signal that initiates their selective degradation. In several cases, it has been shown that the proteolytic signal takes the form of a multi-Ub chain in which successive Ub molecules are linked tandemly at lysine 48 (K-48). Here we show that Ub molecules can be linked together in vivo at two other lysine positions, lysine 29 (K-29) and lysine 63 (K-63). The formation of these alternative linkages is strongly dependent on the presence of the stress-related Ub conjugating enzymes UBC4 and UBC5. Furthermore, expression of Ub carrying a K-63 to arginine 63 substitution in a strain of Saccharomyces cerevisiae that is missing the poly-Ub gene, UBI4, fails to compensate for the stress defects associated with these cells. Taken together, these results suggest that the formation of multi-Ub chains involving K-63 linkages plays an important role in the yeast stress response. In broader terms, these results also suggest that Ub is a versatile signal in which different Ub chain configurations are used for different functions.

Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain.

The covalent attachment of ubiquitin (Ub) to short-lived or damaged proteins is believed to be the signal that initiates their selective degradation. In several cases, it has been shown that the proteolytic signal takes the form of a multi-Ub chain in which successive Ub molecules are linked tandemly at lysine 48 (K-48). Here we show that Ub molecules can be linked together in vivo at two other lysine positions, lysine 29 (K-29) and lysine 63 (K-63). The formation of these alternative linkages is strongly dependent on the presence of the stress-related Ub conjugating enzymes UBC4 and UBC5. Furthermore, expression of Ub carrying a K-63 to arginine 63 substitution in a strain of Saccharomyces cerevisiae that is missing the poly-Ub gene, UBI4, fails to compensate for the stress defects associated with these cells. Taken together, these results suggest that the formation of multi-Ub chains involving K-63 linkages plays an important role in the yeast stress response. In broader terms, these results also suggest that Ub is a versatile signal in which different Ub chain configurations are used for different functions.

Identifying alternative linkages among philosophy, theory and method in nursing science.

The major concerns expressed in the literature regarding the development and expansion of nursing science stem from questions related to 'what sorts of science' and 'which scientific methods' are appropriate for nursing. While there is a sector of nursing's scientific community that advocates a unified approach to philosophy and method, a growing sentiment for the position of philosophical and methodological pluralism is apparent. This paper addresses the nature of scientific pluralism by presenting a framework for alternative linkages possible among the philosophy, theory and method appropriate for nursing science. The nature of nursing knowledge that is produced within the discipline will thus depend on various forms of alternative linkages adopted by nursing scientists in addressing nursing's scientific questions. In turn, such pluralism presents problems of choice to nurses in practice with respect to knowledge utilization.

Democratic Rural Development: Leadership Accountability in Regional Peasant Organizations

ABSTRACTMany development analysts assert the importance of democratic social organizations, but few either document or analyse the actual processes of internal democracy. This study examines part of the broader problem of the ‘Iron Law of Oligarchy’ — the ebbs and flows of leadership accountability over time. Drawing on the history of a Mexican regional peasant organization since 1974, the analysis suggests that different kinds of organizational structures encourage or discourage membership action, but moments of mass direct action in turn shape the ways in which organizational structures actually distribute power. The case analysis shows how the interaction of internal and external factors shaped the balance of power between leaders and members at each critical turning point. Participatory subgroups turn out to be the crucial counterweight to concentrated leadership power, mediating relations with the membership and providing alternative sources of leadership. Whether formal or informal, multiple vertical channels and alternative horizontal linkages between membership groups are crucial complements, and sometimes substitutes, to conventional organizational structures.

The stereoselective addition of organometallic reagents to electron-deficient alkylidenecyclohexanes; alternative linkages for cholaphane synthesis

Knoevenagel condensations between t-butylcyclohexanone and malononitrile, Meldrum's acid and ethyl cyanoacetate gave electron-deficient alkenes which underwent equatorial-selective attack by chemoselective aryl organometallic reagents. Further transformations of the products were shown to be possible in some cases. The methodology is relevant to the synthesis of macrocyclic “cholaphane” receptors with externally-directed functional groups.

Transmembrane molecular assemblies in cell-extracellular matrix interactions

Several new interactions have been identified and proteins characterized in focal adhesions. Together they suggest alternative or parallel linkages between actin filaments and members of the integrin family of extracellular receptors. Transformed cells continue to serve as models for studying the assembly and disassembly of these adhesions.

Exclusive A-ring linkage for singly attached phycocyanobilins and phycoerythrobilins in phycobiliproteins. Absence of singly D-ring-linked bilins.

Previous spectroscopic studies on the phycocyanobilin-containing peptide beta-2T from Synechococcus sp. 6301 C-phycocyanin and the phycoerythrobilin-containing peptide beta-2TP from Porphyridium cruentum B-phycoerythrin indicated a different single thioether mode of attachment, postulated to be through the D-ring of the tetrapyrrole, in contrast to the A-ring linkage established for the other singly linked bilins in these proteins (Bishop, J.E., Lagarias, J.C., Nagy, J. O., Schoenleber, R.W., Rapoport, H., Klotz, A.V., and Glazer, A.N. (1986) J. Biol. Chem. 261, 6790-6796; Klotz, A.V., Glazer, A.N., Bishop, J.E., Nagy, J.O., and Rapoport, H. (1986) J. Biol. Chem. 261, 6797-6805). The crystal structure of Agmenellum quadruplicatum C-phycocyanin at 2.5-A resolution (Schirmer, T., Bode, W., and Huber, R. (1987) J. Mol. Biol., 196, 677-695) supports an A-ring linkage for all three phycocyanobilins. Consequently we have re-evaluated our proposed structural assignments by further 1H NMR studies. Two-dimensional homonuclear correlated and nuclear Overhauser enhancement spectroscopic data presented here show that all three bilins in Synechococcus 6301 C-phycocyanin are attached solely through the A-ring, complementary to the crystallographic data. The evidence from the NMR data for all bilin peptides examined includes the dipoledipole interactions of the 5-H with the 3-H, 3'-H, and a pyrrole methyl group (7-CH3); the corresponding interactions would not be possible in a D-ring-linked bilin. The 5-H also consistently exhibits allylic J-coupling to the 3-H, supporting A-ring linkage assignment. These data are inconsistent with the alternative D-ring linkage assignment since this would involve J-coupling through five bonds. Examination of the phycoerythrobilin beta-2 position in B-phycoerythrin also reveals an A-ring type of attachment by similar criteria. We conclude that all singly linked bilins are attached through the A-ring.