Exemplification and the use-values of cases and case studies

This paper provides an account of the ‘use-value’ of case-based research by showing how social scientists exploit cases, and case studies, in a variety of practices of inference and extension. The critical basis for making such extensions relies on the power of a case, or the account given of a case (the case-study account), to exemplify certain features of the social world in ways which prove valuable for further analysis: either of the same case, or in many domains beyond the original case study. Framing use-values in terms of exemplification compares favourably with understanding reasoning beyond the case either as a form of analogical reasoning or in taking cases as experimentable objects.     

Positive feedback sharpens the anaphase switch

At the onset of anaphase, sister-chromatid cohesion is dissolved abruptly and irreversibly, ensuring that all chromosome pairs disjoin almost simultaneously. The regulatory mechanisms that generate this switch-like behaviour are unclear. Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC), triggers the destruction of securin, thereby allowing separase, a protease, to disrupt sister-chromatid cohesion. Here we demonstrate that the cyclin-dependent kinase 1 (Cdk1)-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14 (refs 5 and 6), our results support the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, we show that mutations that disrupt securin phosphoregulation decrease the synchrony of chromosome segregation. Our results also suggest that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister-chromatid separation with changes in spindle dynamics.     

Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines

Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient’s immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.     

Monoclonal antibodies demonstrate protection of polymorphonuclear leukocytes against complement attack

Studies on erythrocytes have shown that the formation of the membrane attack complex on a cell surface inevitably results in lysis. However, it is known that nucleated cells are much more difficult to kill with complement, although the molecular basis of this resistance has never been established. We have shown that a very early intracellular event, occurring within seconds of formation of the attack complex in the membrane, is a rise in cytoplasmic Ca2+, which can activate cell responses without cell death 5,6. Here we report the use of a monoclonal antibody to the terminal complement component C9, quantified by 125I and visualized by fluorescein, to demonstrate a protection mechanism in polymorphonuclear leukocytes (PMNs) attacked by complement, involving removal of the attack complex by vesiculation. Concomitantly, there is a Ca2+-dependent activation of reactive oxygen metabolite production without cell lysis. These findings have important implications in the evolutionary and pathological significance of the terminal components of the complement pathway.     

Motion-deblurring in human vision

If photographs are taken of moving objects at slow shutter speeds the images of the objects are blurred. In human vision, however, we are not normally conscious of blur from moving objects despite the fact that the temporal response of the photoreceptors is sluggish. It has been suggested that there are motion-deblurring mechanisms specifically to aid the visual system in the analysis of the shape of retinally moving targets. Models of motion deblurring have been influenced by the finding that certain very precise spatial pattern discriminations are unaffected by motion. An example is vernier hyperacuity, in which the observer must detect the direction of offset between two lines with abutting ends. With a stationary stimulus, observers can detect a vernier cue of less than 10 arcsec and acuity is unaffected by retinal-image motion of up to 3 deg s-1 We confirm this finding, but provide evidence against any general deblurring mechanism by showing that another kind of hyperacuity, discrimination of the distance between two parallel lines (spatial interval acuity), is interfered with by motion. This argues against a general deblurring mechanism, such as a neural network 'shifter circuit', and we point out that the high level of vernier acuity for moving stimuli is susceptible to an alternative explanation.     

Seriation in the Presence of Errors: NP-Hardness of <Emphasis Type="Italic">l</Emphasis><Subscript><Emphasis Type="Italic">∞</Emphasis></Subscript> -Fitting Robinson Structures to Dissimilarity Matrices

In this paper, we establish that the following fitting problem is NP-hard: given a finite set X and a dissimilarity measure d on X (d is a symmetric function from X ² to the nonnegative real numbers and vanishing on the diagonal), we wish to find a Robinsonian dissimilarity d _R on X minimizing the l _∞ -error ||d − d _R || _∞ = max_x,y ∈X{|d(x, y) − d _R (x, y)|} between d and d _R . Recall that a dissimilarity d _R on X is called monotone (or Robinsonian) if there exists a total order ≺ on X such that x ≺ z ≺ y implies that d(x, y) ≥ max{d(x, z), d(z, y)}. The Robinsonian dissimilarities appear in seriation and clustering problems, in sparse matrix ordering and DNA sequencing.     

Proton translocation by cytochrome c oxidase.

Cell respiration in mitochondria and some bacteria is catalysed by cytochrome c oxidase, which reduces O2 to water, coupled with translocation of four protons across the mitochondrial or bacterial membrane. The enzyme's catalytic cycle consists of a reductive phase, in which the oxidized enzyme receives electrons from cytochrome c, and an oxidative phase, in which the reduced enzyme is oxidized by O2. Previous studies indicated that proton translocation is coupled energetically only to the oxidative phase, but this has been challenged. Here, with the purified enzyme inlaid in liposomes, we report time-resolved measurements of membrane potential, which show that half of the electrical charges due to proton-pumping actually cross the membrane during reduction after a preceding oxidative phase. pH measurements confirm that proton translocation also occurs during reduction, but only when immediately preceded by an oxidative phase. We conclude that all the energy for proton translocation is conserved in the enzyme during its oxidation by O2. One half of it is utilized for proton-pumping during oxidation, but the other half is unlatched for this purpose only during re-reduction of the enzyme.