Munc18a controls SNARE assembly through its interaction with the syntaxin N-peptide

Sec1/Munc18-like (SM) proteins functionally interact with SNARE proteins in vesicular fusion. Despite their high sequence conservation, structurally disparate binding modes for SM proteins with syntaxins have been observed. Several SM proteins appear to bind only to a short peptide present at the N terminus of syntaxin, designated the N-peptide, while Munc18a binds to a 'closed' conformation formed by the remaining portion of syntaxin 1a. Here, we show that the syntaxin 16 N-peptide binds to the SM protein Vps45, but the remainder of syntaxin 16 strongly enhances the affinity of the interaction. Likewise, the N-peptide of syntaxin 1a serves as a second binding site in the Munc18a/syntaxin 1a complex. When the syntaxin 1a N-peptide is bound to Munc18a, SNARE complex formation is blocked. Removal of the N-peptide enables binding of syntaxin 1a to its partner SNARE SNAP-25, while still bound to Munc18a. This suggests that Munc18a controls the accessibility of syntaxin 1a to its partners, a role that might be common to all SM proteins.     

ASSORTATIVE MATING AND THE ADAPTIVE LANDSCAPE

The ability of a population to shift from one adaptive peak to another was examined for a two-locus model with different degrees of assortative mating, selection, and linkage. As expected, if the proportion of the population that mates assortatively increases, so does its ability to shift to a new peak. Assortative mating affects this process by allowing the mean fitness of a population to increase monotonically as it passes through intermediate gene frequencies on the way to a new, higher, homozygotic peak. Similarly, if the height of the new peak increases or selection against intermediates becomes less severe, the population becomes more likely to shift to a new peak. Close linkage also helps the shift to a new adaptive peak and acts similarly to assortative mating, but it is not necessary for such a shift as was previously thought. When a population shifts to a new peak, the number of generations required is significantly less than that needed to return to the original peak when that happens. The short period of time required may be an explanation for rapid changes in the geological record. Under extremely high degrees of assortative mating, the shift takes longer, presumably because of the difficulty of breaking up less favored allelic combinations.     

A system for coupled multiple-column separation of proteins

Purification of proteins is commonly a multiple-step process involving size exclusion, ion exchange, affinity, hydrophobic, and other modes of chromatography. In an effort to circumvent the laborious process of collecting the solutes from each column and reintroducing them onto a second column, a valving system is described that directs the samples eluted from a high-performance liquid chromatographic column through a detector with a high-pressure cell into either a second column or into storage loops of a multiloop value. This multiloop value is referred to as a high-pressure fraction collector. After development of the first column is complete, a second solvent can be directed to the second column or high-pressure fraction collector to elute the solutes back through the detector and onto any other column in the system. The process of eluting a sample from a column through a single detector and directing it to the high-pressure fraction collector or any other column in the system may be repeated a number of times. Such valving systems make it possible to chromatograph a single protein component on two or three columns in a short time.     

Prediction-based structured variable selection through the receiver operating characteristic curves

In many clinical settings, a commonly encountered problem is to assess accuracy of a screening test for early detection of a disease. In these applications, predictive performance of the test is of interest. Variable selection may be useful in designing a medical test. An example is a research study conducted to design a new screening test by selecting variables from an existing screener with a hierarchical structure among variables: there are several root questions followed by their stem questions. The stem questions will only be asked after a subject has answered the root question. It is therefore unreasonable to select a model that only contains stem variables but not its root variable. In this work, we propose methods to perform variable selection with structured variables when predictive accuracy of a diagnostic test is the main concern of the analysis. We take a linear combination of individual variables to form a combined test. We then maximize a direct summary measure of the predictive performance of the test, the area under a receiver operating characteristic curve (AUC of an ROC), subject to a penalty function to control for overfitting. Since maximizing empirical AUC of the ROC of a combined test is a complicated nonconvex problem (Pepe, Cai, and Longton, 2006, Biometrics62, 221-229), we explore the connection between the empirical AUC and a support vector machine (SVM). We cast the problem of maximizing predictive performance of a combined test as a penalized SVM problem and apply a reparametrization to impose the hierarchical structure among variables. We also describe a penalized logistic regression variable selection procedure for structured variables and compare it with the ROC-based approaches. We use simulation studies based on real data to examine performance of the proposed methods. Finally we apply developed methods to design a structured screener to be used in primary care clinics to refer potentially psychotic patients for further specialty diagnostics and treatment.     

Survival lotteries reconsidered

In 1975 John Harris envisaged a survival lottery to redistribute organs from one to a greater number in order to reduce number of deaths as a consequence of organ failure. In this paper I reach a conclusion about when running a survival lottery is permissible by looking at the reason prospective participants have for allowing the procedure from a contractual perspective. I identify three versions of the survival lottery. In a National Lottery, everyone within a jurisdiction is a candidate for being a donor for everyone else, disregarding all differences between individuals' eventual possibility of needing an organ. In a Group Specific Lottery, it is a question of running a lottery among members of a specific group who share the same probability of getting organ failure. In a Local Lottery one randomises among individuals who are already in need of a new organ but who happen to be compatible and in need of different organs. While the first is vulnerable to considerations of fairness, it is difficult to perceive a feasible way to implement the second option that does not come with a host of unwelcome consequences. I argue, however, that it is permissible to run Local Lotteries.     

Eye-specific learning of routes and “signposts” by walking honeybees

This study investigates the honeybee's ability to learn routes based on visual stimuli presented to a single eye, and to then navigate these routes using the other (naive) eye. Bees were trained to walk through a narrow tunnel carrying visual stimuli on the two walls. At the end of the tunnel the bees had to choose between two arms, one of which led to a feeder. In a first experiment, bees had to learn to choose the left arm to get a reward when the right wall carried a yellow grating, but the right arm when the left wall carried a blue grating. The bees learned this task well, indicating that stimuli encountered by different eyes could be associated with different routes. In a second experiment, bees had to turn left when the right eye saw a blue grating, but to the right when the same eye saw a yellow grating. They also learned this task well. In subsequent tests, they chose the correct arm even when these gratings were presented to the untrained eye. These results suggest that there is interocular transfer of route-specific learning with respect to visual stimuli that function as navigational “signposts”. Accepted: 18 December 1997     

Multicultural society and everyday cultural racism: second generation of Ethiopian Jews in Israel's ‘crisis of modernization’

Abstract

The core of this article sets out to examine the extent to which a multicultural society can prevent cultural racism, which, like multiculturalism, is by definition based on a culture of diversity and separation. The ‘first modernity’ was organized along national lines, with a centralist state that opted to create an essentialist and uncontested national identity. Immigrants, especially those who came from ‘third world’ countries, were expected to undergo a process of assimilation, and to integrate into the dominant culture by relinquishing their particular past and tradition. Multiculturalism, which emerged historically as a criticism of that perspective, aims at creating a kaleidoscope of associations and cultural communities, which inevitably presents a challenge to the one ‘truth’ of the nation-state with the argument that this ‘truth’ favours some groups over others. Within the multicultural model, identity politics of various groups is perceived as a means to achieve recognition, acceptance, respect and even public affirmation of differences. However, do multicultural society and identity-related differences provide a solution to cultural racism as well?

Investigating the second generation of the Ethiopian Jews, who migrated to Israel during its transformation from ethno-national republicanism to a neo-liberal, multicultural society, can help answer this question. By presenting their patterns of association, character of protest activities and the newly formed hybrid identity that Ethiopian youth have developed as a means to liberate themselves from a discriminating reality, and by examining the Others’ reaction to that challenge, this article uncovers certain mechanisms and methods of action through which a multicultural society, having a thin and mild version of multiculturalism, does not diminish cultural racism, particularly its everyday non-institutional version, but in fact augments it.     

Relationship between energy distribution and fold stability: Insights from molecular dynamics simulations of native and mutant proteins

Most proteins must fold to a well-defined structure with a minimal stability to perform their function. Here we use a simple, molecular dynamics-based, energy decomposition approach to map the principal energetic interactions in a set of proteins representative of different folds. This work involves the all-atom simulation and analysis of the native structures and mutants of five different proteins representative of an all-alpha (yACPB, Protein A), all-beta (SH3), and a mixed alpha/beta fold (Proteins G and L). Given a certain structure, a native sequence and a set of mutants, we show that our model discriminates the ability of a mutation to yield a more or less stable protein, in agreement with experimental data, catching the principal energetic determinants of protein stabilization. Our approach identifies the interaction determinants responsible to define a fold and shows that mutations can either modulate the strength of pair-wise coupling between residues important for folding, or modify the profile of the principal interactions. Furthermore, we address the question of how to evaluate the fitness of a sequence to a given structure by comparing the information contained in the energy map, which recapitulates the chemistry of the sequence, to that contained in the contact map, which recapitulates the fold topology. The results show that the better fit between the energetic properties of the sequence and the fold topology corresponds to a higher stabilization of the protein. We discuss the relevance of these observations to the analysis of protein designability and to the rational evolution of new sequences.     

The concept of mental disorder: diagnostic implications of the harmful dysfunction analysis

What do we mean when we say that a mental condition is a medical disorder rather than a normal form of human suffering or a problem in living? The status of psychiatry as a medical discipline depends on a persuasive answer to this question. The answers tend to range from value accounts that see disorder as a sociopolitical concept, used for social control purposes, to scientific accounts that see the concept as strictly factual. I have proposed a hybrid account, the harmful dysfunction (HD) analysis, that incorporates both value and scientific components as essential elements of the medical concept of disorder, applying to both physical and mental conditions. According to the HD analysis, a condition is a disorder if it is negatively valued ("harmful") and it is in fact due to a failure of some internal mechanism to perform a function for which it was biologically designed (i.e., naturally selected). The implications of this analysis for the validity of symptom-based diagnostic criteria and for challenges in cross-cultural use of diagnostic criteria are explored, using a comparison of the application of DSM diagnostic criteria in the U.S. and Taiwan.     

Brooding of pelagic-type larvae in Ophiopeza spinosa: reproduction and development in a tropical ophiodermatid brittlestar

Abstract. Ophiopeza spinosa , a small ophiodermatid ophiuroid, is locally abundant in shallow water rubble habitat at Lizard Island, northern Great Barrier Reef, Australia. This species is a protantric hermaphrodite. The switch from reproduction as a male to a female is progressive, involving a simultaneous hermaphrodite as a transitional stage. Members of O. spinosa brood their young in the respiratory bursae. Cohorts of eggs (280 μm diameter) develop synchronously in the gonad and are spawned as a group into the bursa. Despite non-pelagic development, the larvae of O. spinosa are a vitellaria type typical of broadcast-spawning ophiodermatids, providing a link to an ancestral form with a dispersive larva. The vitellaria has prominent ciliary bands and swims in the same manner as pelagic vitellaria. In vitro , the larvae developed to the juvenile stage independent of the parent. There was no evidence of extraembryonic nutrition; a proportion of the maternal provisions were retained through metamorphosis. This is the first ophiuroid known to brood a pelagic-type vitellaria larva. Juveniles appear to leave the parent at the two- to three-arm segment stage, slightly larger than the newly settled juveniles of ophiodermatids with pelagic vitellariae. The presence of functional larvae in the bursa suggests a recent switch to the incubatory life history in O. spinosa and the possibility of a reversal back to a dispersive life history. O. spinosa have the potential to both brood and broadcast their young.     

Structure of the abdominal receptor responsive to internally applied pressure in the blood-feeding insect,Rhodnius prolixus

Summary The sensory receptor responsive to pressure applied internally to the ventral abdominal body wall of the blood-feeding insects, Rhodnius prolixus, is a single sense cell containing, at its distal end, a cilium enclosed within a scolopale, a densely staining structure characteristic of insect scolopidial sensilla. A small spherical structure lies within a dilation near the midregion of the cilium, and contains nine heavily staining bodies, the position of each corresponding to a pair of microtubules in the cilium. Proximal to the dilation, the microtubules are organized in a ring of nine pairs with one microtubule of each pair associated with dyneinlike arms. Dastal to the dilation a central pair of microtubules is present, but dyneinlike arms are absent. The scolopale cell, which gives risc to the scolopale, has cytoplasmic invaginations that form an elaborate array of extracellular compartments surrounding the body wall of the sense cell. These compartments may serve to dampen high frequency vibrations permitting the receptor to respond to pressure exerted by touch, an attribute in keeping with the receptor's proposed function of detecting abdominal distension related to the size and movement of the stomach.     

Peptide-protein interaction markedly alters the functional properties of the catalytic subunit of aspartate transcarbamoylase.

Interaction of a 70-amino acid zinc-binding polypeptide from the regulatory chain of aspartate transcarbamoylase (ATCase) with the catalytic (C) subunit leads to dramatic changes in enzyme activity and affinity for ligand binding at the active sites. The complex between the polypeptide (zinc domain) and wild-type C trimer exhibits hyperbolic kinetics in contrast to the sigmoidal kinetics observed with the intact holoenzyme. Moreover, the Scatchard plot for binding N-(phosphonacetyl)-L-aspartate (PALA) to the complex is linear with a Kd corresponding to that evaluated for the holoenzyme converted to the relaxed (R) state. Additional evidence that the binding of the zinc domain to the C trimer converts it to the R state was attained with a mutant form of ATCase in which Lys 164 in the catalytic chain is replaced by Glu. As shown previously (Newell, J.O. & Schachman, H.K., 1990, Biophys. Chem. 37, 183-196), this mutant holoenzyme, which exists in the R conformation even in the absence of active site ligands, has a 50-fold greater affinity for PALA than the free C subunit. Adding the zinc domain to the C trimer containing the Lys 164-->Glu substitution leads to a 50-fold enhancement in the affinity for the bisubstrate analog yielding a value of Kd equal to that for the holoenzyme. A different mutant ATCase containing the Gln 231 to Ile replacement was shown (Peterson, C.B., Burman, D.L., & Schachman, H.K., 1992, Biochemistry 31, 8508-8515) to be much less active as a holoenzyme than as the free C trimer. For this mutant holoenzyme, the addition of substrates does not cause its conversion to the R state. However, the addition of the zinc domain to the Gln 231-->Ile C trimer leads to a marked increase in enzyme activity, and PALA binding data indicate that the complex resembles the R state of the holoenzyme. This interaction leading to a more active conformation serves as a model of intergenic complementation in which peptide binding to a protein causes a conformational correction at a site remote from the interacting surfaces resulting in activation of the protein. This linkage was also demonstrated by difference spectroscopy using a chromophore covalently bound at the active site, which served as a spectral probe for a local conformational change. The binding of ligands at the active sites was shown also to lead to a strengthening of the interaction between the zinc domain and the C trimer.     

Influence of seeing a female on the male–male interactions of a jumping spider, Hypoblemum albovittatum

An important prediction from game theory is that resource value influences the level to which competitors will escalate conflict. An earlier study considered whether this prediction applies to the male–male interactions of Hypoblemum albovittatum, a jumping spider (Salticidae) from New Zealand. The males of this species escalated conflicts in the presence of a moving mount made from a conspecific female. However, because the control was only a similar-sized motionless cork, an alternative hypothesis (that the cue for escalation is seeing movement of any female-size object, rather than seeing specifically a female) was not ruled out. Here we show that a moving cork, without a mount present, is indeed sufficient to cause males to escalate, but a moving mount (made from a conspecific female) causes males to escalate further. The level of escalation in the presence of a moving mount made from prey (housefly) or from a rival (conspecific male) did not differ significantly from the level of escalation when only a moving cork was present. These findings suggest that, although seeing a moving object similar in size to a conspecific female is sufficient for priming males to escalate, males can also discern by sight that specifically a female is present and, when they have this precise information, they make strategic decisions to escalate conflict further.     

Morphogenesis of rod-shaped sacculi

For growth and division of rod-shaped bacteria, the cylindrical part of the sacculus has to be elongated and two new cell poles have to be synthesized. The elongation is performed by a protein complex, the elongase that inserts disaccharidepentapeptide units at a limited number of discrete sites while using the cytoskeletal MreB helix as a tracking device. Upon initiation of cell division by positioning of the cytoskeletal Z-ring at mid cell, a switch from dispersed to concentrated local peptidoglycan-synthesis occurs. From this point on, peptidoglycan synthesis is for a large part redirected from elongating activity to synthesis of new cell poles by the divisome. The divisome might be envisioned as an extended elongase because apart from its basic peptidoglycan synthesizing activity, specific functions have to be added. These are conversion from a cylinder to a sphere, invagination of the outer membrane and addition of hydrolases that allow separation of the daughter cells. The elongase and the divisome are dynamic hyperstructures that probably share part of their proteins. Although this multifunctionality and flexibility form a barrier to the functional elucidation of its individual subunits, it helps the cells to survive a variety of emergency situations and to proliferate securely.     

Chromothripsis: Breakage-fusion-bridge over and over again

The acquisition of massive but localized chromosome translocations, a phenomenon termed chromothripsis, has received widespread attention since its discovery over a year ago. Until recently, chromothripsis was believed to originate from a single catastrophic event, but the molecular mechanisms leading to this event are yet to be uncovered. Because a thorough interpretation of the data are missing, the phenomenon itself has wrongly acquired the status of a mechanism used to justify many kinds of complex rearrangements. Although the assumption that all translocations in chromothripsis originate from a single event has met with criticism, satisfactory explanations for the intense but localized nature of this phenomenon are still missing. Here, we show why the data used to describe massive catastrophic rearrangements are incompatible with a model comprising a single event only and propose a molecular mechanism in which a combination of known cellular pathways accounts for chromothripsis. Instead of a single traumatic event, the protection of undamaged chromosomes by telomeres can limit repetitive breakage-fusion-bridge events to a single chromosome arm. Ultimately, common properties of chromosomal instability, such as aneuploidy and centromere fission, might establish the complex genetic pattern observed in this genomic state.     

Male-biased operational sex ratios and the Viking phenomenon: an evolutionary anthropological perspective on Late Iron Age Scandinavian raiding

In this paper, we use a combination of evolutionary theory, ethnographic data, written sources, and archaeological evidence to develop a new explanation for the origins of Viking raiding. Our argument focuses on the operational sex ratio, which is the ratio of males to females in a society who are ready to mate at a given time. We propose that a combination of two practices – polygyny and concubinage – and the increase in social inequality that occurred in Scandinavia during the Late Iron Age resulted in a male-biased operational sex ratio. This would have created a pool of unmarried men motivated to engage in risky behaviours that had the potential to increase their wealth and status, and therefore their probability of entering the marriage market. With high-status men looking to instigate expeditions to acquire plunder and develop their reputations as war leaders, raiding represented a mutually beneficial means of achieving social advancement and success.     

Spatial self-organization in a cyclic resource-species model

Biological communities are remarkable in their ability to form cooperative ensembles that lead to coexistence through various types of niche partitioning, usually intimately tied to spatial structure. This is especially true in microbial settings where differential expression and regulation of genes allows members of a given species to alter their lifestyle so as to fill a functional role within the community. The resulting species interactions can involve feedback, as in the case of some bacterial consortia that participate in the cooperative degradation of a given resource in a succession of steps and in such a way that certain "later" species provide catalytic support for the primary degrader. We seek to capture the essential features of such spatially extended biological systems by introducing a lattice-based stochastic spatial model (interacting particle system) with cyclic local dynamics. Here, a given site progresses through a sequence of resource and species states in a prescribed order. Furthermore, this succession of states (at a site) is assumed to form a cyclic pattern due to a natural feedback mechanism. We explore conditions under which all the species are able to coexist and consider the extent to which this coexistence requires the development of spatio-temporal patterns, including spiral waves. This self-organization, if it occurs, results when synchronization of the dynamics at the microscopic level leads to macroscopic patterns. These patterns result in consumer-driven resource fluctuations that generate a form of spatio-temporal niche partitioning. As with most models of this complexity, we employ a mixture of mathematical analysis and simulations to develop an understanding of the resulting dynamics.     

The extinction context enables extinction performance after a change in context

One experiment with human participants determined the extent to which recovery of extinguished responding with a context switch was due to a failure to retrieve contextually controlled learning, or some other process such as participants learning that context changes signal reversals in the meaning of stimulus-outcome relationships. In a video game, participants learned to suppress mouse clicking in the presence of a stimulus that predicted an attack. Then, that stimulus underwent extinction in a different context (environment within the game). Following extinction, suppression was recovered and then extinguished again during testing in the conditioning context. In a final test, participants that were tested in the context where extinction first took place showed less of a recovery than those tested in a neutral context, but they showed a recovery of suppression nevertheless. A change in context tended to cause a change in the meaning of the stimulus, leading to recovery in both the neutral and extinction contexts. The extinction context attenuated that recovery, perhaps by enabling retrieval of the learning that took place in extinction. Recovery outside an extinction context is due to a failure of the context to enable the learning acquired during extinction, but only in part.