Killer Cell Immunoglobulin-Like Receptor Alleles Alter HIV Disease in Children

Background

HLA class I molecules are ligands for killer cell immunoglobin like receptors (KIR) that control the antiviral response of natural killer (NK) cells. However, the effects of KIR and HLA (KIR/HLA) alleles on HIV disease of children have not been studied.

Methods

993 antiretroviral naïve children with symptomatic HIV infection from PACTG protocols P152 and P300 were genotyped for KIR and HLA alleles using the Luminex platform. Linear regression was used to test the association between genotypes and baseline pre-ART HIV RNA, CD4⁺ lymphocyte count, and cognitive score, adjusting for age, race/ethnicity and study. The interaction between genetic markers and age was investigated. To account for multiple testing the false discovery rate (FDR) was controlled at 0.05.

Results

Children with the KIR2DS4*ALL FULL LENGTH (KIR2DS4*AFL) allele had higher CD4⁺ lymphocyte counts. Among children ≤2 years of age, the KIR2DS4*AFL was associated with lower plasma HIV RNA and higher cognitive index scores. KIR Cent2DS3/5_1 had lower CD4⁺ lymphocyte counts in children ≤2 years of age, while the presence of Tel1, Tel2DS4_2, Tel2DS4_4, Tel8, Tel2DS4_6 had higher CD4⁺ lymphocyte counts in all children. Presence of Cent2, Cent4 and Cent8 was associated with increased HIV RNA load in children ≤2 years. Presence of KIR3DL1+Bw4 was associated with higher CD4⁺ lymphocyte counts in all children. Among children >2 years old, KIR3DS1+Bw4-80I was associated with higher plasma HIV RNA, and Bw6/Bw6 was associated with lower plasma HIV RNA compared to children with KIR3DS1+Bw4-80I.

Conclusions

Presented data show for the first time that specific KIR alleles independently or combined with HLA ligands are associated with HIV RNA and CD4⁺ lymphocyte counts in infected, antiretroviral naive children; and many of these effect estimates appear to be age dependent. These data support a role for specific KIR alleles in HIV pathogenesis in children.     

An MRI-Compatible High Frequency AC Resistive Heating System for Homeothermic Maintenance in Small Animals

PurposeTo develop an MRI-compatible resistive heater, using high frequency alternating current (AC), for temperature maintenance of anaesthetised animals.ResultsImages and spectra acquired in the presence and absence of 50–100 kHz AC through the wire heater were indistinguishable, whereas DC power created field shifts and lineshape distortions. Temperature lost during induction of anaesthesia was recovered within approximately 20 minutes and a stable temperature was reached as the mouse’s temperature approached the set target.ConclusionThe AC-powered wire heater maintains adequate heat input to the animal to maintain body temperature, and does not compromise image quality.     

Angiotensin II Induced Cardiac Dysfunction on a Chip

In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.     

Including competitive asymmetry in measures of local interference in plant populations

Summary Although considerable evidence exists that plant competition is generally asymmetric or one-sided, with larger plants having a disproportionate competitive effect on smaller plants, currently employed measures of local interference generally assume that competition is two-sided. We describe a simple measure of competitive asymmetry in which the effects of neighbors smaller than a focal individual are discounted by a constant factor, and include this variable in a composite measure of local interference. In this model competition varies between complete asymmetry (the effects of smaller plants are entirely discounted) and complete symmetry (the competitive effect of a neighbor is proportional to its size). The proposed method is applied to two natural populations and one experimental monoculture. In all cases an asymmetric model provides the best fit to the data. Completely two-sided models account for 26–39% of the variance in relative growth rate, while relatively one-sided models account for 44–57%. The increases in r ² values resulting from the inclusion of asymmetry are significant in the two cases in which the data permit randomization tests. Our results suggest that interference is completely asymmetric in a population of Impatiens pallida, a species with very low root allocation and a shallow crown, and somewhat less asymmetric in an experimental monoculture of Ambrosia artemisiifolia and a natural stand of Pinus rigida, cases in which competition for water and nutrient resources is likely to be of greater importance.     

Plant Proteinase inhibitors: A defense against herbivorous insects?

Using the tomato plant, Lycopersicon esculentum L., and the beet armyworm, Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae), we have demonstrated that insect herbivory induces a rapid decline in plant quality. This decline in plant quality manifests itself by a highly significant reduction in rate of larval growth on a medium containing foliage from insect-damaged as opposed to undamaged tomato plants. The induction of tomato proteinase inhibitors, as a result of larval feeding, is invoked as a factor that systemically reduces leaf quality.

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Zusammenfassung Eine zentrale Theorie in der Erforschung von Insekten-Wirtspflanzen-Wechselbeziehungen ist, dass sich bestimmte natürlich vorkommende Pflanzeninhaltsstoffe in Pflanzen zur Abwehr herbivorer Insekten und anderer Parasiten entwickelt haben. Zur Zeit herrschende Überlegungen beinhalten auch das Konzept, dass herbivore Insekten das Potential besitzen, Veränderungen in der Abwehrund/oder Nahrungsqualität von Wirtspflanzen hervorzurufen, die den herbivoren Insekten schaden. Gegenwärtig is nur wenig über die Ursachen dieser von Insekten induzierten Veränderungen der Wirtspflanzenqualität bekannt. Jedoch werden häufig unterschiedliche Gehalte der Pflanzen an Phenolderivaten, Protein und/oder Proteinaseinhibitoren mit den Abwehrmechanismen in Zusammenhang gebracht. Diese Arbeit untersucht das Potential von Pflanzenproteinaseinhibitoren, als induzierbare Abwehr gegen herbivore Noctuidenlarven zu wirken.Tomatenpflanzen enthalten Proteinaseinhibitoren (PIs), die durch Verletzen der Pflanze induziert werden. Es besteht die Hypothese, dass diese Synthese von PIs einen Abwehrmechanismus gegen blattfressende Insekten darstellt. Diese Hypothese ist niemals angemessen in planta getestet worden und wird von uns anhand von Spodoptera exigua und Tomatenpflanzen, Lycopersicon esculentum, getestet.Wieterhin sollte festgestellt werden, ob eine Beziehung zwischen der PI-Konzentration im Blatt und dem Wachstum von Blattmaterial fressenden Larven besteht. Anstelle lebender Pflanzen wurde dazu eine feste, Blattmaterial enthaltende Diät (15% gefriergetrocknetes Blattmaterial angemischt in Agarlösung und Sorbinsäure) benutzt, was die Verwending einer unverletzten Kontrolle ermöglichte. Diese künstliche Diät wurde S. exigua angeboten. Die Ergebnisse des Fütterungsversuches (Fig. 2) zeigen, dass eine signifikante inverse Beziehung (r²=0.81, p=0.05) zwischen der PI-Konzentration im Blattgewebe und den mittleren Gewichten von Larven von S. exigua besteht. Nicht dargestellt ist die nicht signifikante Korrelation zwischen mittlerem Gewicht der Larven und den Gehalten an Blattprotein (r²=0.47, p>0.25) und Phenolderivaten (r²=0.50, p=0.25).Diese Ergebnisse veranlassen uns zu dem Rückschluss, dass Tomatenproteinaseinhibitoren als systemisch induzierbare antibiotische chemische Abwehr gegen herbivore Insekten wie Noctuidenlarven anzusehen sind, und dass PIs einen Faktor darstellen, der zur systemischen Reduktion der Blattqualität von Tomaten führt.

     

Isozyme variation and correspondence with unusual infrared reflectance patterns inPhragmites australis (Poaceae)

Isozyme variation was investigated in populations ofPhragmites australis (Poaceae) which have recently invaded and taken over marsh habitat of the Mississippi River delta. Infrared aerial photographs in the Garden Island Bay subdelta of the extensiveP. australis populations reveal distinct, clone-like circular patches within a predominant background. Preliminary evidence indicates that the infrared color differences represent distinct morphological types. However, there are no obvious environmental factors that could account for the peculiar patterns.P. australis collections were taken from five separate and distinct patches and adjacent background. Only two electrophoretic phenotypes were found: one from patches and one from the background. In comparing the two, 20% of the 40 loci scored are fixed for alternate alleles. These results indicate a clear correspondence of infrared reflectance with electrophoretic phenotype. In addition, the genetic uniformity as evidenced by the discovery of only two electrophoretic phenotypes supports the contention that the recent spread ofP. australis throughout the Mississippi River delta has been primarily, if not exclusively, a result of vegetative propagation.     

Membrane Delivery to the Yeast Autophagosome from the Golgi�CEndosomal System

While many of the proteins required for autophagy have been identified, the source of the membrane of the autophagosome is still unresolved with the endoplasmic reticulum (ER), endosomes, and mitochondria all having been evoked. The integral membrane protein Atg9 is delivered to the autophagosome during starvation and in the related cytoplasm-to-vacuole (Cvt) pathway that occurs constitutively in yeast. We have examined the requirements for delivery of Atg9-containing membrane to the yeast autophagosome. Atg9 does not appear to originate from mitochondria, and Atg9 cannot reach the forming autophagosome directly from the ER or early Golgi. Components of traffic between Golgi and endosomes are known to be required for the Cvt pathway but do not appear required for autophagy in starved cells. However, we find that pairwise combinations of mutations in Golgi-endosomal traffic components apparently only required for the Cvt pathway can cause profound defects in Atg9 delivery and autophagy in starved cells. Thus it appears that membrane that contains Atg9 is delivered to the autophagosome from the Golgi-endosomal system rather than from the ER or mitochondria. This is underestimated by examination of single mutants, providing a possible explanation for discrepancies between yeast and mammalian studies on Atg9 localization and autophagosome formation.     

Optical acquisition and polar decomposition of the full-field deformation gradient tensor within a fracture callus

Tracking tissue deformation is often hampered by material inhomogeneity, so local measurements tend to be insufficient thus lending to the necessity of full-field optical measurements. This study presents a novel approach to factoring heterogeneous deformation of soft and hard tissues in a fracture callus by introducing an anisotropic metric derived from the deformation gradient tensor (F). The deformation gradient tensor contains all the information available in a Green–Lagrange strain tensor, plus the rigid-body rotational components. A recent study [Bottlang et al., Journal of Biomechanics 41(3), 2008] produced full-field strains within ovine fracture calluses acquired through the application of electronic speckle pattern interferometery (ESPI). The technique is based on infinitesimal strain approximation (Engineering Strain) whose scheme is not independent of rigid-body rotation. In this work, for rotation extraction, the stretch and rotation tensors were separately determined from F by the polar decomposition theorem. Interfragmentary motions in a fracture gap were characterized by the two distinct mechanical factors (stretch and rotation) at each material point through full-field mapping. In the composite nature of bone and soft tissue, collagen arrangements are hypothesized such that fibers locally aligned with principal directions will stretch and fibers not aligned with the principal direction will rotate and stretch. This approach has revealed the deformation gradient tensor as an appropriate quantification of strain within callus bony and fibrous tissue via optical measurements.