Genetic Prediction: What are the Limits?

The spectre of determinism stalks many of the concerns surrounding the impact of genetic research into both disease and normal behaviour. The ability accurately to predict a person's actions would certainly have profound implications for notions of individuality and free will. But to what extent will the current explosion in genetic research provide more accurate predictors than have been available for millennia in the form of wealth, social status and perceived family resemblance? The genetic research program is at too early a stage to answer this question with confidence, but various indicators tend to point in the same direction: the predictive ability of genetic analysis will generally be low. This conclusion runs counter to widely perceived popular notions. The deconstruction of genetic determinism is an essential safeguard against the real concern that genetic information may be used for discrimination by unscrupulous powers.     

Genetically Compromising Phospholipid Metabolism Limits Candida albicans’ Virulence

Mycopathologia - Perturbing ergosterol synthesis has been previously shown to reduce the virulence of Candida albicans. We tested the hypothesis that further altering cell membrane composition by...     

Limits of Life and Death: Legallois’s Decapitation Experiments

In Expériences sur le principe de la vie (Chez D’Hautel, Paris, 1812), Jean César Legallois, a French physician and physiologist, explored the basic regulatory framework of vital processes of warm-blooded animals. He decapitated rabbits and cut off their limbs in order to search for a seat of life that is located in the spinal cord. Through ligatures and artificial pulmonary insufflations, he kept the trunks of rabbits alive for some minutes. Legallois thus criticized models of organic order in which the spinal cord only mediates, like a gross nerve, between the brain and the body. He identified a certain section of the spinal cord that influences respiratory acts, and he also established a connection between the spinal cord and the movement of the heart. Further on, Legallois envisioned experiments that would extend the life-time of headless trunks through the infusion of arterial blood.     

Environmental Limits of Tall Shrubs in Alaska’s Arctic National Parks

We sampled shrub canopy volume (height times area) and environmental factors (soil wetness, soil depth of thaw, soil pH, mean July air temperature, and typical date of spring snow loss) on 471 plots across five National Park Service units in northern Alaska. Our goal was to determine the environments where tall shrubs thrive and use this information to predict the location of future shrub expansion. The study area covers over 80,000 km² and has mostly tundra vegetation. Large canopy volumes were uncommon, with volumes over 0.5 m³/m² present on just 8% of plots. Shrub canopy volumes were highest where mean July temperatures were above 10.5°C and on weakly acid to neutral soils (pH of 6 to 7) with deep summer thaw (>80 cm) and good drainage. On many sites, flooding helped maintain favorable soil conditions for shrub growth. Canopy volumes were highest where the typical snow loss date was near 20 May; these represent sites that are neither strongly wind-scoured in the winter nor late to melt from deep snowdrifts. Individual species varied widely in the canopy volumes they attained and their response to the environmental factors. Betula sp. shrubs were the most common and quite tolerant of soil acidity, cold July temperatures, and shallow thaw depths, but they did not form high-volume canopies under these conditions. Alnus viridis formed the largest canopies and was tolerant of soil acidity down to about pH 5, but required more summer warmth (over 12°C) than the other species. The Salix species varied widely from S. pulchra, tolerant of wet and moderately acid soils, to S. alaxensis, requiring well-drained soils with near neutral pH. Nearly half of the land area in ARCN has mean July temperatures of 10.5 to 12.5°C, where 2°C of warming would bring temperatures into the range needed for all of the potential tall shrub species to form large canopies. However, limitations in the other environmental factors would probably prevent the formation of large shrub canopies on at least half of the land area with newly favorable temperatures after 2°C of warming.     

Can Oxygen Set Thermal Limits in an Insect and Drive Gigantism?

Background

Thermal limits may arise through a mismatch between oxygen supply and demand in a range of animal taxa. Whilst this oxygen limitation hypothesis is supported by data from a range of marine fish and invertebrates, its generality remains contentious. In particular, it is unclear whether oxygen limitation determines thermal extremes in tracheated arthropods, where oxygen limitation may be unlikely due to the efficiency and plasticity of tracheal systems in supplying oxygen directly to metabolically active tissues. Although terrestrial taxa with open tracheal systems may not be prone to oxygen limitation, species may be affected during other life-history stages, particularly if these rely on diffusion into closed tracheal systems. Furthermore, a central role for oxygen limitation in insects is envisaged within a parallel line of research focussing on insect gigantism in the late Palaeozoic.

Methodology/Principal Findings

Here we examine thermal maxima in the aquatic life stages of an insect at normoxia, hypoxia (14 kPa) and hyperoxia (36 kPa). We demonstrate that upper thermal limits do indeed respond to external oxygen supply in the aquatic life stages of the stonefly Dinocras cephalotes, suggesting that the critical thermal limits of such aquatic larvae are set by oxygen limitation. This could result from impeded oxygen delivery, or limited oxygen regulatory capacity, both of which have implications for our understanding of the limits to insect body size and how these are influenced by atmospheric oxygen levels.

Conclusions/Significance

These findings extend the generality of the hypothesis of oxygen limitation of thermal tolerance, suggest that oxygen constraints on body size may be stronger in aquatic environments, and that oxygen toxicity may have actively selected for gigantism in the aquatic stages of Carboniferous arthropods.     

“Upper Limits of Normal” Antistreptolysin O and Antideoxyribonuclease B Titers

"Upper limits of normal" antistreptolysin O (ASO) and antideoxyribonuclease (ADN) B titers were determined on serum specimens from various age groups of pediatric patients with no history of a recent streptococcal infection and on healthy adult hospital employees. The upper limit of normal value is that level of antibody titer exceeded by no more than 15% of the total subjects in each age group. This value varies with the age of the subject, and the most pronounced differences are between the values of preschool age children, school age children, and adults. The upper limit of normal values for these groups were as follows: preschool age, ASO = 85(100); ADN B = 60(50); school age, ASO = 170(166); ADN B=1 70(166); and adult, ASO = 85(100); ADN B = 85(100).     

Protein Phosphatase 1? Limits Ring Canal Constriction during Drosophila Germline Cyst Formation

Germline cyst formation is essential for the propagation of many organisms including humans and flies. The cytoplasm of germline cyst cells communicate with each other directly via large intercellular bridges called ring canals. Ring canals are often derived from arrested contractile rings during incomplete cytokinesis. However how ring canal formation, maintenance and growth are regulated remains unclear. To better understand this process, we carried out an unbiased genetic screen in Drosophila melanogaster germ cells and identified multiple alleles of flapwing (flw), a conserved serine/threonine-specific protein phosphatase. Flw had previously been reported to be unnecessary for early D. melanogaster oogenesis using a hypomorphic allele. We found that loss of Flw leads to over-constricted nascent ring canals and subsequently tiny mature ring canals, through which cytoplasmic transfer from nurse cells to the oocyte is impaired, resulting in small, non-functional eggs. Flw is expressed in germ cells undergoing incomplete cytokinesis, completely colocalized with the Drosophila myosin binding subunit of myosin phosphatase (DMYPT). This colocalization, together with genetic interaction studies, suggests that Flw functions together with DMYPT to negatively regulate myosin activity during ring canal formation. The identification of two subunits of the tripartite myosin phosphatase as the first two main players required for ring canal constriction indicates that tight regulation of myosin activity is essential for germline cyst formation and reproduction in D. melanogaster and probably other species as well.     

Temperature or Transport? Range Limits in Marine Species Mediated Solely by Flow

Clusters of range boundaries in coastal marine species often occur at shoreline locations where major nearshore ocean currents collide. Observing that these currents are typically composed of waters with quite different physical characteristics, biologists have traditionally assumed that high local densities of marine range limits result primarily from the strong water property gradients (particularly in temperature) that arise at oceanographic discontinuities. However, this view may overlook the potential for ocean flows themselves to generate distributional pattern. Here we explore this possibility in more detail using an extension of a coupled population dispersal model developed previously for benthic marine species with dispersing larvae. Results suggest that simple, common flow fields often observed in association with biogeographic boundaries worldwide may have the potential to constrain a species' geographic range, even when suitable habitat outside that range is abundant. Model predictions suggest that these boundaries can function as one- or two-way barriers to range expansion and may be differentially permeable, with boundary leakiness depending on life-history characteristics and the degree of temporal variability in the nearshore flow field.     

Limits to evolution at range margins: when and why does adaptation fail?

What stops populations expanding into new territory beyond the edge of a range margin? Recent models addressing this problem have brought together population genetics and population ecology, and some have included interactions among species at range edges. Here, we review these models of adaptation at environmental or parapatric margins, and discuss the contrasting effects of migration in either swamping local adaptation, or supplying the genetic variation that is necessary for adaptation to continue. We illustrate how studying adaptation at range margins (both with and without hybridization) can provide insight into the genetic and ecological factors that limit evolution more generally, especially in response to current rates of environmental change.     

Can the United States Establish the Outer Limits of Its Extended Continental Shelf Under International Law?

Although most provisions of the United Nations Convention on the Law of the Sea are regarded customary international law and the United States views most of its provisions as such, the outsider status of the United States causes problems in some areas, especially concerning the continental shelf beyond 200 nautical miles. This article asks whether it is possible for the United States to establish the outer limits of its continental shelf beyond 200 nautical miles in line with international law without becoming a state party to the convention, and if that is possible, how could the United States proceed?     

��v��3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that β3 integrin can regulate negatively VEGFR2 expression. Here we show that β3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of αvβ3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when β3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of β3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that αvβ3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that β3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.     

Does Dream Interpretation Have Any Limits? An Evaluation of Interpretations of the Dream of “Irma's Injection”

Dream interpretative efforts appear unconstrained by methodological standards. An examination of the re-interpretations of Freud's dream of Irma's Injection, the dream specimen of psychoanalysis, illustrates the undisciplined nature of dream interpretation. Reading in from presumed day residues or infantile experiences rather than out from the dream report per se lies at the heart of the problem. The failure to spell out inferences, to link inferences to the dream text, to explain and maintain the relationships in the dream report, and to offer a substitute text for the entire dream text all contribute to the inadequacies of dream interpreatation.     

Protein Kinase Cδ Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance

Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca²⁺-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.     

Comments: Limits of phosphorus removal in wetlands (Kadlec,previous issue,pp. 165–175)

Wetlands Ecology and Management -     

What Limits the Number of Tītī (Puffinus griseus) Harvested by Rakiura Māori?

Mori continue a centuries old harvest of tt chicks (sooty shearwater, Puffinus griseus) on islands adjacent to Rakiura (Stewart Island). This study measured time limits on the number of Tttaken each day from Putauhinu Island. In the first period of the harvest (nanao) the chicks are extracted from the breeding burrows during daytime. In the second period of harvest (rama) the chicks are caught at night after they have emerged from their nesting burrows. Capture rate is much higher during the rama than the nanao. More time is spent processing (plucking, cutting-up, gutting, and packing) chicks during rama than the nanao because of a 1.3–1.7 increase in the number of chicks caught. Recently introduced motorized plucking machines decrease the time required to pluck each chick and make plucking less physically demanding and less painful. However, motorized pluckers did not increase the number of chicks harvested on Putauhinu. Other social limits may control harvest intensity and influence sustainability of muttonbirding.     

Limits in virus filtration capability? Impact of virus quality and spike level on virus removal with xenotropic murine leukemia virus

Virus filtration (VF) is a key step in an overall viral clearance process since it has been demonstrated to effectively clear a wide range of mammalian viruses with a log reduction value (LRV) > 4. The potential to achieve higher LRV from virus retentive filters has historically been examined using bacteriophage surrogates, which commonly demonstrated a potential of > 9 LRV when using high titer spikes (e.g. 10¹⁰ PFU/mL). However, as the filter loading increases, one typically experiences significant decreases in performance and LRV. The 9 LRV value is markedly higher than the current expected range of 4‐5 LRV when utilizing mammalian retroviruses on virus removal filters (Miesegaes et al., Dev Biol (Basel) 2010;133:3‐101). Recent values have been reported in the literature (Stuckey et al., Biotech Progr 2014;30:79‐85) of LRV in excess of 6 for PPV and XMuLV although this result appears to be atypical. LRV for VF with therapeutic proteins could be limited by several factors including process limits (flux decay, load matrix), virus spike level and the analytical methods used for virus detection (i.e. the Limits of Quantitation), as well as the virus spike quality. Research was conducted using the Xenotropic‐Murine Leukemia Virus (XMuLV) for its direct relevance to the most commonly cited document, the International Conference of Harmonization (ICH) Q5A (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, 1999) for viral safety evaluations. A unique aspect of this work is the independent evaluation of the impact of retrovirus quality and virus spike level on VF performance and LRV. The VF studies used XMuLV preparations purified by either ultracentrifugation (Ultra 1) or by chromatographic processes that yielded a more highly purified virus stock (Ultra 2). Two monoclonal antibodies (Mabs) with markedly different filtration characteristics and with similar levels of aggregate (<1.5%) were evaluated with the Ultra 1 and Ultra 2 virus preparations utilizing the Planova 20 N, a small virus removal filter. Impurities in the virus preparation ultimately limited filter loading as measured by determining the volumetric loading condition where 75% flux decay is observed versus initial conditions (V₇₅). This observation occurred with both Mabs with the difference in virus purity more pronounced when very high spike levels were used (>5 vol/vol %). Significant differences were seen for the process performance over a number of lots of the less‐pure Ultra 1 virus preparations. Experiments utilizing a developmental lot of the chromatographic purified XMuLV (Ultra 2 Development lot) that had elevated levels of host cell residuals (vs. the final Ultra 2 preparations) suggest that these contaminant residuals can impact virus filter fouling, even if the virus prep is essentially monodisperse. Process studies utilizing an Ultra 2 virus with substantially less host cell residuals and highly monodispersed virus particles demonstrated superior performance and an LRV in excess of 7.7 log₁₀. A model was constructed demonstrating the linear dependence of filtration flux versus filter loading which can be used to predict the V₇₅ for a range of virus spike levels conditions using this highly purified virus. Fine tuning the virus spike level with this model can ultimately maximize the LRV for the virus filter step, essentially adding the LRV equivalent of another process step (i.e. protein A or CEX chromatography). © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 31:135–144, 2015