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PubMed2000

Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats.

The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS-) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.

Acoustic Stimulation↗

PubMed2005

Dissociating cognitive deficits involved in voluntary eye movement dysfunctions in Parkinson's disease patients.

In an attempt to distinguish and define the altered cognitive processes associated with Parkinson's disease (PD), we examine and try to dissociate the components of an effective voluntary saccade: (1) the planning and execution of a voluntary saccade; (2) the suppression of reflexive eye movements; and (3) the working memory processes required. We tested 14 PD patients (off their medications) and 11 control subjects on antisaccade (AS), delayed antisaccade (DAS), and remembered antisaccade (RAS) paradigms. The three tasks required identical responses, each task only differing in a single manipulation for direct comparison--a delay period was added in the DAS, and the target was removed during the delay period of the RAS--allowing us to study the specific cognitive processes involved in the execution of a voluntary saccade. Voluntary saccade response times were longer in the PD group compared to controls on all three tasks, suggesting difficulties in voluntary saccade execution. Furthermore, PD patients showed difficulty suppressing reflexive saccades (increased number of errors in the AS task and increased number of disinhibitions in the DAS task). Finally, our study did not show significant differences in either response time or error rate between the RAS and the DAS tasks for either control subjects or PD patients. In sum, we report evidence for voluntary saccade execution deficits together with problems inhibiting reflexive saccades in Parkinson's disease patients. These findings were correlated with each other and disease severity, suggesting that eye movement measurement may be a useful tool for studying higher cognitive function.

Aged↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2025

Outcomes of Experiencing Interpersonal Violence in Autism: A Mixed Methods Systematic Review and Meta-Analysis.

In this review and meta-analysis, we aimed to examine outcomes of interpersonal violence among autistic people. Intersectionality and minority theories suggest that negative outcomes are heightened among people with multiple marginalized identities. Thus, we also aimed to investigate gender-related outcomes of interpersonal violence among autistic people. We conducted a systematic database search with inclusion criteria including mixed methods, peer-reviewed research examining any harmful interpersonal act (e.g., physical, sexual, and psychological) experienced by autistic people. We undertook a random-effects meta-analysis with pooled data from 9 studies, comprising 3,647 autistic participants aged 1 to 80 years. Violence was associated with worsened mental health, with the strongest association for internalizing symptoms (d = 0.66, p < .001; 95% CI [0.51, 0.80]) and suicidal thoughts and behavior (d = 0.63, p < .001; [0.44, 0.82]). Narrative synthesis of 57 studies comprising 37,418 participants (13,127 autistic, 24,291 non-autistic) found violence was associated with numerous adverse health, development, and functional outcomes, including worsened mental health and behavioral difficulties compared to non-autistic controls from childhood. Females and gender minorities reported greater intra- and interpersonal health and development difficulties related to violence, emerging in early childhood and enduring into adulthood. Findings provide strong evidence of lifelong negative outcomes associated with interpersonal violence experienced by autistic people, providing evidence for the relevance of minority stress and intersectionality theories in understanding risk. Indeed, our results raise concerns that autistic people, and particularly non-male (female, gender diverse) individuals, have higher susceptibility for abuse from a young age, while being conditioned to respond with social desirability, superficial adaptivity, and dissociation.

Humans↗

PubMed2001

Dissociation of nicotine tolerance from tobacco dependence in humans.

Chronic functional tolerance to nicotine generally is believed to be associated with processes responsible for tobacco dependence. The dose-related effects of nicotine (0-20 microg/kg by nasal spray) on subjective, cardiovascular, and performance responses were compared among four groups varying in current or past dependence: dependent smokers (21 cigarettes per day for 20 years; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 cigarettes per day for 19 years; n = 17), and life-long nonsmokers (n = 19). Chronic tolerance was determined by a shift to the right, or flattening, of the dose-response curve relative to the curve for nonsmokers. Responses were corrected for plasma nicotine concentration to rule out dispositional tolerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was substantial and virtually identical between dependent and nondependent smokers, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and nondependent smokers indicates that tolerance is not a linear function of smoking exposure and does not require presence of dependence. Thus, the wide variability in daily smoking rate among smokers cannot be attributed to differences in tolerance and must involve other processes of adaptation to nicotine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after extended abstinence, despite loss of dependence. These results suggest there is no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.

Adult↗

PubMed1990

The growth-associated protein GAP-43 appears in dorsal root ganglion cells and in the dorsal horn of the rat spinal cord following peripheral nerve injury.

When adult dorsal root ganglion cells are dissociated and maintained in vitro, both the small dark and the large light neurons show increases in the growth-associated protein GAP-43, a membrane phosphoprotein associated with neuronal development and plasticity. Immunoreactivity for GAP-43 appears in the cytoplasm of the cell bodies as early as 3.5 h post axotomy and is present in neurites and growth cones as soon as they develop. At early stages of culture (4 h to eight days) satellite/Schwann cells are also immunoreactive for GAP-43. Neurons in isolated whole dorsal root ganglion maintained in vitro become GAP-43-immunoreactive between 2 and 3 h after axotomy. It takes three days however, after cutting or crushing the sciatic nerve in adult rats in vivo, for GAP-43 immunoreactivity to appear in the axotomized dorsal root ganglion cells. GAP-43 immunoreactivity can be detected in the central terminals of primary afferent neurons in the superficial laminae of the dorsal horn of the lumbar enlargement four days after sciatic cut or crush. The intensity of the GAP-43 staining reaches a peak at 21 days and becomes undetectable nine weeks following crush injury and 36 weeks following sciatic nerve cut. The pattern of GAP-43 staining is identical to the distribution of sciatic small-calibre afferent terminals. Little or no staining is present in the deep dorsal horn, but GAP-43 does appear in the ipsilateral gracile nucleus 22 days after sciatic injury. In investigating the mechanism of GAP-43 regulation, blockade of axon transport in the sciatic nerve with vinblastine (10(-5) M-10(-4) M) or capsaicin (1.5%) was found to produce a pattern of GAP-43 immunoreactivity in the dorsal horn identical to that found with crush, while electrical stimulation of the sciatic nerve had no effect. Axotomy of primary sensory neurons or the interruption of axon transport in the periphery therefore acts to trigger GAP-43 production in the cell body. The GAP-43 is transported to both the peripheral and the central terminals of the afferents. In the CNS the elevated GAP-43 levels may contribute to an inappropriate synaptic reorganization of afferent terminals that could play a role in the sensory disorders that follow nerve injury.

Animals↗

PubMed2005

Romancing the family: Umberto Eco's Baudolino.

Referencing Umberto Eco's novel Baudolino, the author discusses issues concerning the authenticity of the narrative, specifically the distortions in the story presented to the audience and doubts surrounding the veracity of the tale. The act of narration is associated with the shame caused by the abuse and neglect that is an integral part of this story. The ambivalence of the protagonist--to tell his story and to keep it (and his true identity) concealed--associates narration, a creative act, with lying. Trauma generates the lies and hiddenness as a means of coping with abuse and indifference. In order to deal with the feelings of inadequacy caused by his humble birth, the traumatized protagonist lies: he romanticizes his family origins, the illusion of being the offspring of distinguished parents. His attempt to win the love of the parents, by being both good and all-knowing, is one of the motivating forces of his family romance. Telling lies makes the protagonist omniscient: he is the only one who knows if and when he is telling the truth. Paradoxically, the narrator creates and undermines that image of omniscience by revealing the thought processes of one character while leaving opaque those of the protagonist, and by denying the trueness of the tale affirmed when he presents as objective his own subjective sentiments by indirectly attributing them to the protagonist. The uncertainty that underpins the narration is indicative of the storyteller's absence. This vacancy structures the work because it allows kindred spirits, nonjudgmental readers (listeners) who willingly suspend disbelief, to enter the world of the narrator. This uncritical participation counters the chaos of the storyteller's reality, as they create their own new world where the split parental images are united.

Adaptation, Psychological↗

PubMed1989

A.E. Bennett award paper. Experimental approaches to human stress research: assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients.

This article presents a series of experiments that involves the development of three novel strategies for human stress research and the utilization of these strategies to examine neurobehavioral processes of stress in healthy volunteers, schizophrenia, and affective illness. The first strategy involved intravenous 2-deoxy-D-glucose (2DG) administration, a glucoprivic stressor. We found that glucoprivic stress results in dissociation of hypothalamus-pituitary-adrenal (HPA), adrenomedullary, and sympathoneural activity. In addition, glucoprivic stress in neuroleptic-treated schizophrenic patients caused heightened dopamine activity, as reflected by increased plasma homovanillic acid (HVA) levels and decreased adaptive responses as assessed by decreased food consumption following 2DG administration. These data suggest that neuroleptics do not prevent stress-related increases in dopamine activity and that schizophrenia may be associated with abnormalities in the stress response. The second strategy assessed effects of uncontrollable and identical amounts of controllable stress in volunteers and depressed patients. In volunteers, it was found that uncontrollable in comparison to controllable stress results in specific behavioral and neuroendocrine alterations. Moreover, uncontrollable stress exposure in depressed patients in comparison to volunteers produced greater alterations in behavioral ratings and plasma cortisol levels and that the uncontrollable stress related increases in helplessness ratings and cortisol levels were significantly correlated. These data suggest that depressed patients may have increased sensitivity to uncontrollable stress and that there may be an important interrelationship between the cognitive deficits of depression and the heightened HPA axis activity observed in these patients. Lastly, we used a naturalistic strategy to examine mechanisms relating childhood parental loss and the development of adult affective illness and found that among subjects with early parental loss histories, those who developed adult psychiatric illness had increased resting plasma levels of cortisol and beta-endorphin (ir) as compared with subjects with early loss and no adult history of psychiatric illness. Moreover, increased HPA activity in adulthood was significantly related to poor childhood adjustment to parental loss. The implications of the results of these studies are discussed.

Adrenocorticotropic Hormone↗

PubMed2003

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).

Adult↗

PubMed1989

The compulsion to repeat the trauma. Re-enactment, revictimization, and masochism.

Trauma can be repeated on behavioral, emotional, physiologic, and neuroendocrinologic levels. Repetition on these different levels causes a large variety of individual and social suffering. Anger directed against the self or others is always a central problem in the lives of people who have been violated and this is itself a repetitive re-enactment of real events from the past. People need a "safe base" for normal social and biologic development. Traumatization occurs when both internal and external resources are inadequate to cope with external threat. Uncontrollable disruptions or distortions of attachment bonds precede the development of post-traumatic stress syndromes. People seek increased attachment in the face of external danger. Adults, as well as children, may develop strong emotional ties with people who intermittently harass, beat, and threaten them. The persistence of these attachment bonds leads to confusion of pain and love. Assaults lead to hyperarousal states for which the memory can be state-dependent or dissociated, and this memory only returns fully during renewed terror. This interferes with good judgment about these relationships and allows longing for attachment to overcome realistic fears. All primates subjected to early abuse and deprivation are vulnerable to engage in violent relationships with peers as adults. Males tend to be hyperaggressive, and females fail to protect themselves and their offspring against danger. Chronic physiologic hyperarousal persists, particularly to stimuli reminiscent of the trauma. Later stresses tend to be experienced as somatic states, rather than as specific events that require specific means of coping. Thus, victims of trauma may respond to contemporary stimuli as a return of the trauma, without conscious awareness that past injury rather than current stress is the basis of their physiologic emergency responses. Hyperarousal interferes with the ability to make rational assessments and prevents resolution and integration of the trauma. Disturbances in the catecholamine, serotonin, and endogenous opioid systems have been implicated in this persistence of all-or-none responses. People who have been exposed to highly stressful stimuli develop long-term potentiation of memory tracts that are reactivated at times of subsequent arousal. This activation explains how current stress is experienced as a return of the trauma; it causes a return to earlier behavior patterns. Ordinarily, people will choose the most pleasant of two alternatives. High arousal causes people to engage in familiar behavior, regardless of the rewards. As novel stimuli are anxiety provoking, under stress, previously traumatized people tend return to familiar patterns, even if they cause pain.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMedDate not supplied

[Emotional processes in schizophrenia: investigation of the evaluative component].

Schizophrenia is a disease that constitutes a particularly relevant way to investigate emotional processing. Indeed, major clinical signs of emotional disturbance (eg, anhedonia) suggest that some emotional mechanisms are defective in patients with schizophrenia. Evaluation can be considered as a fundamental component of the emotional system (28) and the first aim of the present study was to test the polarity hypothesis according to which different mechanisms are involved in the evaluation of positive vs negative emotional events. The second aim was to disentangle a -paradox emerging from the schizophrenia literature. On one hand, the tendency that schizophrenic patients have to under-evaluate the level of unpleasantness of negative stimuli suggests a deficit in the evaluation of negative events. For instance, it was proposed that patients with schizophrenia show a major deficit in the recognition of negative emotions, but a preserved recognition of positive emotions. On the other hand, the fact that anhedonia constitutes a critical cli-nical feature of schizophrenia suggests a deficit in the eva-luation of positive events. For instance, Crespo-Facorro et al. showed that patients with schizophrenia had a tendency to under-evaluate the level of pleasantness of positive stimuli but correctly evaluated the level of unpleasantness of negative stimuli. Given the importance of the social component in the analysis of deficits in patients with schizophrenia, we hypothesized that the variation of this component in stimuli used in the literature could explain the apparently inconsistent results described above. For example, the Bell et al. study used social stimuli whereas the Crespo-Facorro et al. study used non-social stimuli. Therefore, in our study, we have decided to manipulate the social component of stimuli. Another research issue of the present experiment was to study the explicit and/or implicit mode of processing of eva-luation in schizophrenic patients. In general, the experimental logic was to expect interaction effects between the factors polarity (negative vs positive) and participants (schizophrenic patients vs controls). Moreover, given the potential importance of the social component, a three-way interaction of the factors polarity, participants, and social component was expected. Finally, the experimental paradigm allowed us to search for dissociations in the context of both explicit and implicit evaluation. Stimuli used were negative and positive emotional pictures from the International Affective Picture System. Stimuli were chosen so that the mean valence -ratings of negative and positive pictures were at the same distance from neutrality. The factor arousal was controlled so that negative and positive pictures had equivalent mean arousal ratings. The social component factor was operatio-nalized by selecting pictures that either depicted or not a social scene. A fundamental criterion was that all social pictures were depicting at least one human being (eg, a wedding or a funeral), whereas non-social pictures never depicted any human being (eg, animals and landscapes). An upper and a lower border, that were either identical or different, were added to each picture. In a first experiment (the "implicit-task experiment"), patients with schizophrenia and matched controls were requested to decide whether the two borders surrounding the pictures were identical or different. Asking participants to process the borders was an experimental ruse to test if emotional processing takes place even when it is not task-relevant, and therefore if it is implicit. In a second experiment (the "explicit-task experiment"), the same participants were requested to evaluate whether the pictures were pleasant or unpleasant. Analyses of variance (ANOVA) were computed on response time and number of correct responses for both tasks. An important result was the observation of the expected three-way interaction effect of the factors polarity, participants, and social component on response time in the explicit task F(1, 19)=4.8, p<0.05. Critically, we observed that, for non-social stimuli, the interaction effect of the factors participants and polarity on response time was significant in the explicit task, F(1, 8)=4.9, p<0.05. These results are consistent with the polarity hypothesis and suggest a deficit in the processing of non-social positive stimuli in patients with schizophrenia. The expected three-way interaction effect was also observed on the number of correct responses in the explicit task F(1, 19)=5, p<0.04. For this task, we critically observed that, for social stimuli, the interaction effect of the factors participants and polarity on the number of correct responses was significant F(1, 19)=8.4, p<0.04. These results are also consistent with the polarity hypothesis and suggest a deficit in the processing of social negative stimuli in patients with schizophrenia. Moreover, let us notice that a comparison of the performances of the two groups revealed that patients made significantly more errors than controls for the evaluation of non-social positive stimuli, F(1, 19)=10,5, p<0.001, but not for the evaluation of non-social negative stimuli, F<1. In the implicit-task experiment, the analysis revealed that patients had a tendency to make more errors in the judgment of borders configuration for negative than for positive stimuli, whereas control participants showed the opposite tendency F(1, 19)=5.7, p<0.03, for the interaction of the factors polarity and participants. This result is consistent with the idea that distinct cognitive mechanisms are involved in the evaluation of positive vs negative emotional events even in the context of implicit processing. In conclusion, results obtained support the hypothesis according to which different cognitive mechanisms are involved in the evaluation of positive vs negative emotional events. Moreover, results suggest that patients with schizophrenia show a deficit in hedonic judgment of social negative and non-social positive stimuli. The later result indicates that the paradox described above becomes clearer whenever the social component of emotional stimuli happens to be taken into account. Results suggest that the polarity and the social component of events evaluated by patients with schizophrenia are critical parameters that should be considered in forthcoming studies that investigate affect disorders in schizophrenia.

Adult↗

PubMed2005

Protein promiscuity: drug resistance and native functions--HIV-1 case.

The association of a drug with its target protein has the effect of blocking the protein activity and is termed a promiscuous function to distinguish from the protein's native function (Tawfik and associates, Nat. Genet. 37, 73-6, 2005). Obviously, a protein has not evolved naturally for drug association or drug resistance. Promiscuous protein functions exhibit unique traits of evolutionary adaptability, or evolvability, which is dependent on the induction of novel phenotypic traits by a small number of mutations. These mutations might have small effects on native functions, but large effects on promiscuous function; for example, an evolving protein could become increasingly drug resistant while maintaining its original function. Ariel Fernandez, in his opinion piece, notes that drug-binding "promiscuity" can hardly be dissociated from native functions; a dominant approach to drug discovery is the protein-native-substrate transition-state mimetic strategy. Thus, man-made ligands (e.g. drugs) have been successfully crafted to restrain enzymatic activity by focusing on the very same structural features that determine the native function. Using the successful inhibition of HIV-1 protease as an example, Fernandez illustrates how drug designers have employed naturally evolved features of the protein to suppress its activity. Based on these arguments, he dismisses the notion that drug binding is quintessentially promiscuous, even though in principle, proteins did not evolve to associate with man made ligands. In short, Fernandez argues that there may not be separate protein domains that one could term promiscuous domains. While acknowledging that drugs may bind promiscuously or in a native-like manner a la Fernandez, Tawfik maintains the role of evolutionary adaptation, even when a drug binds native-like. In the case of HIV-1 protease, drugs bind natively, and the initial onset of mutations results in drug resistance in addition to a dramatic decline in enzymatic activity and fitness of the virus. A chain of compensatory mutations follows this, and then the virus becomes fully fit and drug resistant. Ben Berkhout and Rogier Sanders subscribe to the evolution of new protein functions through gene duplication. With two identical protein domains, one domain can be released from a constraint imposed by the original function and it is thus free to move in sequence space toward a new function without loss of the original function. They emphasize that the forced evolution of drug-resistance differs significantly from the spontaneous evolution of an additional protein function. For instance, the latter process could proceed gradually on an evolutionary time scale, whereas the acquisition of drug-resistance is an all or nothing process for a virus, leading to the failure or success of therapy. They find no evidence to the thesis that resistance-mutations appear more rapidly in promiscuous domains than native domains. Berkhout and Sanders illustrate the genetic plasticity of HIV-1 by citing examples in which well-conserved amino acid residues of catalytic domains are forced to mutate under drug-pressure. HIV drug resistance biology is very complex. Instead of a viral protein, a drug can be targeted at a cellular protein. For example, Berkhout and Sanders claim, a drug targeted at the cellular protein CCR5 inhibits the binding of the viral envelope glycoprotein (Env) to CCR5. However, Env mutates so that it binds to the CCR5-drug complex and develops drug resistance. Interestingly, CCR5 has not evolved to bind to Env, but to a series of chemokines. Andrzej Kloczkowski, Taner Sen, and Bob Jernigan point out the importance of protein motions for binding. They believe it is likely that different ligands can bind to the diverse protein conformations sampled in the course of normal protein conformational fluctuations. They have been applying simple elastic network models to extract the motions as normal modes, which yield relatively small numbers of conformations that are useful for developing protein mechanisms; while these are typically small motions, for some proteins they can be quite large in scale. One of the major advantages of the approach is that only relatively small numbers of modes are important contributors to the overall motion -- so the approach provides a way to systematically map out a protein's motions. These models successfully represent the conformational fluctuations manifested in the crystallographic B-factors, and often suggest motions related to protein functional behaviors, such as those observed for reverse transcriptase, where two dominant hinges clearly relate to the processing steps -- one showing anti-correlation between the polymerase and ribonuclease H sites related to the translation and positioning of the nucleic acid chain, and another for opening and closing the polymerase site. Disordered proteins represent a more extreme case where the set of accessible conformations is much larger; thus they could offer up a broader range of possible binding forms. Whether evolution controls the functional motions for proteins remains little studied. Intriguingly, buried in the existing databases of protein-protein interactions may be information that can shed light on the extent of promiscuous binding among proteins themselves. Within these data there are cases where large numbers of diverse proteins have been shown to interact with a single protein; some of these could represent promiscuous protein-protein binding. Uncovering these promiscuous behaviors could be important for comprehending the details of how proteins can bind promiscuously to one another, and can exhibit even greater promiscuity in their binding to small molecules. The evolutionary routes, the dynamics of the target protein, and the many other aspects that need to be addressed while designing a drug that may dodge drug resistance, indicate the complexity and multi-disciplinary nature of the issue of drug resistance.

Adaptation, Physiological↗