Molecular mechanisms of steric pressure generation and membrane remodeling by disordered proteins.

Cellular membranes, which are densely crowded by proteins, take on an elaborate array of highly curved shapes. Steric pressure generated by protein crowding plays a significant role in shaping membrane surfaces. It is increasingly clear that many proteins involved in membrane remodeling contain substantial regions of intrinsic disorder. These domains have large hydrodynamic radii, suggesting that they may contribute significantly to steric congestion on membrane surfaces. However, it has been unclear to what extent they are capable of generating steric pressure, owing to their conformational flexibility. To address this gap, we use a recently developed sensor based on Förster resonance energy transfer to measure steric pressure generated at membrane surfaces by the intrinsically disordered domain of the endocytic protein, AP180. We find that disordered domains generate substantial steric pressure that arises from both entropic and electrostatic components. Interestingly, this steric pressure is largely invariant with the molecular weight of the disordered domain, provided that coverage of the membrane surface is held constant. Moreover, equivalent levels of steric pressure result in equivalent degrees of membrane remodeling, regardless of protein molecular weight. This result, which is consistent with classical polymer scaling relationships for semi-dilute solutions, helps to explain the molecular and physical origins of steric pressure generation by intrinsically disordered domains. From a physiological perspective, these findings suggest that a broad range of membrane-associated disordered domains are likely to play a significant and previously unknown role in controlling membrane shape.

Conformational evolution of polymorphic amyloid assemblies.

The morphological diversity of amyloid assemblies has complicated the development of disease therapies and the design of novel biomaterials for decades. Here we review the conformational evolution of amyloids from the initial liquid-liquid phase separation into the oligomeric particle phase to the nucleation of the more ordered assembly phases. With mounting evidence that the assemblies emerging from the oligomeric phases may not be stable in solution and undergo further structural transitions, we propose the concept of conformational evolution, where mutations may occur at the ends or on the surface of the pre-existing fibers and different morphologies are under selection throughout the assembly process.

Competing Motivations: Proactive Response Inhibition Toward Addiction-Related Stimuli in Quitting-Motivated Individuals.

We examined whether addiction-related cues impact proactive inhibition (the restraint of actions in preparation for stopping) in individuals who are motivated to quit gambling or cannabis use. In Study 1, treatment-seeking individuals with cannabis use disorder and matched controls performed a stop-signal task that required them to inhibit categorizing cannabis or neutral pictures, and within varying levels of stop-signal probability. In Study 2, two groups of individuals, who applied to a voluntary self-exclusion program toward gambling, performed the stop-task following relaxation or gambling craving induction, with results compared to non-gamblers. Study 1 showed that despite being less efficient in proactive inhibition, individuals with cannabis use disorder exhibited heightened proactive inhibition toward cannabis cues. In Study 2, proactive inhibition toward gambling cues was heightened in gamblers after craving, but the degree of proactive adjustment decreased as a function of induced changes in gambling-related motivation. Present findings demonstrate that exposure to addiction-related cues can modulate proactive inhibition in individuals who are motivated to restrict their addictive behaviors.

Neural correlates of proactive and reactive motor response inhibition of gambling stimuli in frequent gamblers.

We used functional magnetic resonance imaging to examine whether motivational-salient cues could exert a differential impact on proactive (the restrain of actions in preparation for stopping) and reactive (outright stopping) inhibition. Fourteen high-frequency poker players, and 14 matched non-gambler controls, performed a modified version of the stop-signal paradigm, which required participants to inhibit categorization of poker or neutral pictures. The probability that a stop-signal occurs (0%, 17%, 25%, 33%) was manipulated across blocks of trials, as indicated by the color of the computer screen. Behavioral analyses revealed that poker players were faster than controls in categorizing pictures across all levels of proactive motor response inhibition (go trials). Brain imaging analyses highlighted higher dorsal anterior cingulate cortex activation in poker players, as compared to controls, during reactive inhibition. These findings suggest that, due to their faster rates of stimulus discrimination, poker players might have recruited more cognitive resources than controls when required to stop their response (reactive inhibition). Nevertheless, no main effect of stimulus type was found, on either proactive or reactive inhibition. Additional studies are, therefore, needed in order to confirm that investigating the dynamics between reactive and proactive inhibition offers a discriminative analysis of inhibitory control toward motivational-salient cues.

Amyloid scaffolds as alternative chlorosomes.

Living systems contain remarkable functional capability built within sophisticated self-organizing frameworks. Defining the assembly codes that coordinate these systems could greatly extend nanobiotechnology. To that end, we have highlighted the self-assembling architecture of the chlorosome antenna arrays and report the emulation and extension of their features for the development of cell-compatible photoredox materials. We specifically review work on amyloid peptide scaffolds able to (1) organize light-harvesting chromophores, (2) break peptide bilayer symmetry for directional energy and electron transfer, and (3) incorporate redox active metal ions at high density for energy storage.

[Self-help program: a new tool to facilitate the access to treatment for problem gamblers]. / Programme self-help: un nouvel outil pour faciliter l'accès au traitement des joueurs excessifs.

Shame, fear of stigmatization, denial, accessibility to and the cost of treatment program may explain why only a small proportion of problem gamblers sought clinical treatment. In the hope to overcome these barriers, the Gambling Clinic and Other Behavioral Addictions of C.H.U. Brugmann (Brussels) has developed its own self-help program for excessive gamblers. Our goals were to foster readiness to change gambling behaviors and when appropriate to facilitate the transition from self-help program to classical face-to-face clinical intervention. In a sample of 172 problem gamblers who participated, 40% had never sought help (e.g., clinical treatment) and/or never attempted quit gambling. Interestingly, for some, internet-based self-help treatment preceded their determination for seeking a traditional face-to-face therapeutic setting. Those results led us to discuss this program as a valid clinical tool within a broader health care setting in excessive gamblers.

Deciphering the Sox-Oct partner code by quantitative cooperativity measurements.

Several Sox-Oct transcription factor (TF) combinations have been shown to cooperate on diverse enhancers to determine cell fates. Here, we developed a method to quantify biochemically the Sox-Oct cooperation and assessed the pairing of the high-mobility group (HMG) domains of 11 Sox TFs with Oct4 on a series of composite DNA elements. This way, we clustered Sox proteins according to their dimerization preferences illustrating that Sox HMG domains evolved different propensities to cooperate with Oct4. Sox2, Sox14, Sox21 and Sox15 strongly cooperate on the canonical element but compete with Oct4 on a recently discovered compressed element. Sry also cooperates on the canonical element but binds additively to the compressed element. In contrast, Sox17 and Sox4 cooperate more strongly on the compressed than on the canonical element. Sox5 and Sox18 show some cooperation on both elements, whereas Sox8 and Sox9 compete on both elements. Testing rationally mutated Sox proteins combined with structural modeling highlights critical amino acids for differential Sox-Oct4 partnerships and demonstrates that the cooperativity correlates with the efficiency in producing induced pluripotent stem cells. Our results suggest selective Sox-Oct partnerships in genome regulation and provide a toolset to study protein cooperation on DNA.

How cognitive assessment through clinical neurophysiology may help optimize chronic alcoholism treatment.

Alcohol dependence constitutes a serious worldwide public health problem. The last few decades have seen many pharmacological studies devoted to the improvement of alcoholism treatment. Although psychosocial treatments (e.g. individual or group therapy) have historically been the mainstay of alcoholism treatment, a successful approach for alcohol dependence consists in associating pharmacologic medications with therapy, as 40-70% of patients following only psychosocial therapy typically resume alcohol use within a year of post-detoxification treatment. Nowadays, two main pharmacological options, naltrexone and acomprosate, both approved by the US Food and Drug Administration, are available and seemingly improve on the results yielded by standard techniques employed in the management of alcoholism. However, insufficient data exist to confirm the superiority of one drug over the other, and research is ongoing to determine what type of alcohol-dependent individual benefits the most from using either medication. Available data on the application of both drugs clearly suggest different practical applications. Thus, a fundamental question remains as to how we can identify which alcoholic patients are likely to benefit from the use of naltrexone, acamprosate or both, and which are not. The aim of the present manuscript is to suggest the use of cognitive event-related potentials as an interesting way to identify subgroups of alcoholic patients displaying specific clinical symptoms and cognitive disturbances. We propose that this may help clinicians improve their treatment of alcoholic patients by focusing therapy on individual cognitive disturbances, and by adapting the pharmaceutical approach to the specific needs of the patient.

Stabilization of a protein nanocage through the plugging of a protein-protein interfacial water pocket.

The unique structural properties of the ferritin protein cages have provided impetus to focus on the methodical study of these self-assembling nanosystems. Among these proteins, Escherichia coli bacterioferritin (EcBfr), although architecturally very similar to other members of the family, shows structural instability and an incomplete self-assembly behavior by populating two oligomerization states. Through computational analysis and comparison to its homologues, we have found that this protein has a smaller than average dimeric interface on its 2-fold symmetry axis mainly because of the existence of an interfacial water pocket centered around two water-bridged asparagine residues. To investigate the possibility of engineering EcBfr for modified structural stability, we have used a semiempirical computational method to virtually explore the energy differences of the 480 possible mutants at the dimeric interface relative to that of wild-type EcBfr. This computational study also converged on the water-bridged asparagines. Replacing these two asparagines with hydrophobic amino acids resulted in proteins that folded into α-helical monomers and assembled into cages as evidenced by circular dichroism and transmission electron microscopy. Both thermal and chemical denaturation confirmed that, in all cases, these proteins, in agreement with the calculations, possessed increased stability. One of the three mutations shifts the population in favor of the higher-order oligomerization state in solution as evidenced by both size exclusion chromatography and native gel electrophoresis. These results taken together suggest that our low-level design was successful and that it may be possible to apply the strategy of targeting water pockets at protein--protein interfaces to other protein cage and self-assembling systems. More generally, this study further demonstrates the power of jointly employing in silico and in vitro techniques to understand and enhance biostructural energetics.

Major depression is associated with impaired processing of emotion in music as well as in facial and vocal stimuli.

BACKGROUND: The processing of emotional stimuli is thought to be negatively biased in major depression. This study investigates this issue using musical, vocal and facial affective stimuli. METHODS: 23 depressed in-patients and 23 matched healthy controls were recruited. Affective information processing was assessed through musical, vocal and facial emotion recognition tasks. Depression, anxiety level and attention capacity were controlled. RESULTS: The depressed participants demonstrated less accurate identification of emotions than the control group in all three sorts of emotion-recognition tasks. The depressed group also gave higher intensity ratings than the controls when scoring negative emotions, and they were more likely to attribute negative emotions to neutral voices and faces. LIMITATIONS: Our in-patient group might differ from the more general population of depressed adults. They were all taking anti-depressant medication, which may have had an influence on their emotional information processing. CONCLUSIONS: Major depression is associated with a general negative bias in the processing of emotional stimuli. Emotional processing impairment in depression is not confined to interpersonal stimuli (faces and voices), being also present in the ability to feel music accurately.

Chronic alcoholism: insights from neurophysiology.

INTRODUCTION: Increasing knowledge of the anatomical structures and cellular processes underlying psychiatric disorders may help bridge the gap between clinical signs and basic physiological processes. Accordingly, considerable insight has been gained in recent years into a common psychiatric condition, i.e., chronic alcoholism. MATERIAL AND METHODS: We reviewed various physiological parameters that are altered in chronic alcoholic patients compared to healthy individuals--continuous electroencephalogram, oculomotor measures, cognitive event-related potentials and event-related oscillations--to identify links between these physiological parameters, altered cognitive processes and specific clinical symptoms. RESULTS: Alcoholic patients display: (1) high beta and theta power in the resting electroencephalogram, suggesting hyperarousal of their central nervous system; (2) abnormalities in smooth pursuit eye movements, in saccadic inhibition during antisaccade tasks, and in prepulse inhibition, suggesting disturbed attention modulation and abnormal patterns of prefrontal activation that may stem from the same prefrontal "inhibitory" cortical dysfunction; (3) decreased amplitude for cognitive event-related potentials situated along the continuum of information-processing, suggesting that alcoholism is associated with neurophysiological deficits at the level of the sensory cortex and not only disturbances involving associative cortices and limbic structures; and (4) decreased theta, gamma and delta oscillations, suggesting cognitive disinhibition at a functional level. DISCUSSION: The heterogeneity of alcoholic disorders in terms of symptomatology, course and outcome is the result of various pathophysiological processes that physiological parameters may help to define. These alterations may be related to precise cognitive processes that could be easily monitored neurophysiologically in order to create more homogeneous subgroups of alcoholic individuals.

Alcoholism leads to early perceptive alterations, independently of comorbid depressed state: an ERP study.

INTRODUCTION: Alcoholism is associated with a deficit in the processing of emotional facial expressions (EFE) and with a delayed P3b component, partially mediated by earlier perceptive deficits (P100, N170). Since alcohol dependence often occurs with depression, we aim at investigating whether classical event-related potentials (ERP) alterations observed in alcoholism are modulated or not by depression. METHODS: Four groups (controls; alcoholics; depressed; alcoholics-depressed) of 12 participants performed two different discrimination tasks, a gender and an emotional one. They had to decide as quickly as possible about the gender or the emotion displayed by facial stimuli during an ERP recording session (32 channels). Reaction times (RTs), P100, N100, N170 and P3b were recorded. RESULTS: At the behavioural level, control participants discriminated EFE (but not gender) more rapidly than the three other groups. At the ERP level, the differences observed on RTs for emotional task were neurophysiologically indexed by a delayed P3b component. This delay was associated with earlier ERP alterations (P100, N100, N170), but only in participants suffering from alcohol dependence, in association or not with depression. DISCUSSION: On the one hand, individuals with alcoholism, associated or not with a comorbid depression, were impaired in the processing of EFE. This deficit was neurophysiologically indexed by early perceptive (P100, N100, N170) and decisional (P3b) alterations. On the other hand, non-alcoholic patients with depression only exhibited P3b impairment. These results lead to potential implications concerning the usefulness of the ERP for the differential diagnosis in psychiatry, notably concerning the comorbidities in alcoholism.

Is the P300 deficit in alcoholism associated with early visual impairments (P100, N170)? An oddball paradigm.

OBJECTIVE: Studies exploring chronic alcoholism with event-related potentials (ERPs) have shown delayed latency and reduced amplitude of the P300, a long-lasting positive potential reflecting decisional processing. This P300 deficit in alcoholism is generally interpreted as a disturbance in central nervous system inhibition or in memory/attention. The present study aimed at identifying if this electrophysiological deficit is already present on earlier components, and advances a new hypothesis concerning the interpretation of the P300 alteration. METHODS: Patients suffering from alcoholism and matched healthy controls had to detect, in an oddball paradigm, emotional faces among a succession of neutral faces. Behavioral performance and ERP data (recorded from 32 electrodes) were analyzed. RESULTS: In line with previous studies, data showed that alcoholism led to a P300 deficit. Moreover, we observed for the first time that this deficit begins at earlier visual (P100) and face-processing (N170) stages, and we found high positive correlations between P100, N170 and P300 for amplitude and latency values, suggesting cumulative deficits on the cognitive continuum. CONCLUSIONS: We suggest that the P300 deficit observed in chronic alcoholism could be linked to earlier visuo-spatial deficits rather than being an impairment of the specific processes linked to the P300. SIGNIFICANCE: These results call for reconsidering the interpretation of P300 impairments at a fundamental and clinical level, and shows that earlier ERP components must be taken into account in future studies.

Supervisory attentional system in nonamnesic alcoholic men.

BACKGROUND: Many studies have shown that recently detoxified alcoholic persons perform poorly on tasks thought to be sensitive to frontal lobe damage, supporting the hypothesis that the frontal lobes are highly vulnerable to chronic alcohol consumption. However, it appeared that most of the executive tasks used in these studies also involved nonexecutive components, and these tasks had been shown to be impaired as a result of nonfrontal lobe lesions. In this study, we examined further the "frontal lobe vulnerability" hypothesis using executive tasks, proved to be associated with frontal lobe functioning, that allowed us to distinguish the relative importance of executive and nonexecutive processes. METHOD: Thirty recently detoxified asymptomatic male alcoholic inpatients and 30 control subjects were tested for planning, inhibition, rule detection, and coordination of dual task, as well as the speed of processing and nonexecutive functions (such as short-term memory storage). RESULTS: Alcoholics performed worse than controls in almost all tasks assessing executive functions. However, they were not slower than the controls and showed normal results for nonexecutive functions. CONCLUSIONS: Chronic alcohol consumption seems to be associated with severe executive function deficits, which are still present after a protracted period of alcohol abstinence. These data support the idea that the cognitive deficits in recently detoxified sober alcoholic subjects are due, at least partly, to frontal lobe dysfunctioning.

Correlation between inhibition, working memory and delimited frontal area blood flow measure by 99mTc-Bicisate SPECT in alcohol-dependent patients.

Recently detoxified non-neurological alcoholic patients appear to be impaired in cognitive tasks measuring inhibitory processes as well as working memory (involving storage and manipulation of information). The aim of this study was to investigate in alcoholic participants the relationship between these two cognitive functions and regional cerebral blood flow (rCBF) studied at rest in regions of interest selected on the basis of recent PET studies which explored inhibitory and working memory in normal subjects. Twenty non-neurological alcoholic patients and 20 normal volunteers were selected for a neuropsychological exploration, including assessment of inhibition processes (by means of the Hayling test) and working memory (by means of the Alpha-span task). rCBF of alcoholics was also evaluated with a semi-quantitative method using a 99mTc-Bicisate single photon emission computed tomography (SPECT) procedure. Alcoholic patients performed worse than controls in the alphabetical condition of the Alpha-span task (involving manipulation and storage of information), and on the Hayling test. Significant correlation emerged between inhibition performance and both the bilateral inferior (left BA 47, r = -0.40; right BA 47, r = -0.599) and median frontal gyrus (left BA 10, r = -0.55; right BA 10, r = -0.59), but not with the region of reference (occipital/cerebellum, r = -0.13). Coordination of storage and manipulation was correlated with bilateral median frontal (left BA 10/46, r = -0.50; right BA 10/46, r = -0.45), but not with bilateral parietal area (left BA 7, r = -0.12, right BA 7, r = -0.18). These results suggest a relationship between inhibition and working memory deficits in alcoholic patients, and regional rCBF measured in frontal areas. Clinical implications of these data related to alcohol relapse are discussed.

An atypical neuropsychological profile of a Korsakoff syndrome patient throughout the follow-up.

The basis of amnesia in alcoholic Wernicke-Korsakoff syndrome (WKS) has been generally associated with diencephalic lesions and more specifically with lesions of the anterior thalamic nuclei. These brain structures are considered to be involved in encoding/consolidation processes of episodic memory. However, frontal lobe damage responsible for executive function deficits has also been documented. The present report details the nature and extent of amnesia in an alcoholic patients with WKS and which appears to be mainly due to frontal lobe (executive) deficits.

Deficits in recognition of emotional facial expression are still present in alcoholics after mid- to long-term abstinence.

OBJECTIVE: Emotional facial expression (EFE) decoding skills play a key role in interpersonal relationships. Decoding errors have been described in several pathological conditions, including alcoholism. The aim of this study was to investigate whether EFE decoding skill deficits persist after abstention from alcohol of at least 2 months. METHOD: Alcoholic patients abstinent for at least 2 months (n = 25) were compared with 25 recently detoxified patients and with 25 normal controls matched for age, gender and educational level. Subjects were presented with 40 photographs of facial expressions portraying happiness, anger, sadness, disgust and fear. Each emotion was displayed with neutral, mild, moderate and strong emotional intensity. Each facial expression was judged successively on eight scales labeled happiness, sadness, fear, anger, disgust, surprise, shame and contempt. For each scale, subjects rated the estimated intensity level. A complementary scale assessed the self-estimated difficulty in performing the task. RESULTS: Recently detoxified alcoholics were significantly less accurate than controls, making more EFE labeling errors and overestimating the intensity of the portrayed emotions. Deficits in decoding accuracy for anger and disgust were present in mid- to long-term abstinent patients; intensity overestimation was present in the former and absent in the latter. CONCLUSIONS: Deficits in decoding accuracy for anger and disgust, and to a lesser degree sadness, persist with an abstinence of 2 months and beyond. Right frontotemporal regions and cingulate could be implicated. These deficits may contribute to the social skills deficits frequently encountered in alcoholic patients.

[Osteocartilaginous reconstruction, research and clinical application]. / Reconstruction ostéocartilagineuse, recherche et application clinique.

Facing the problem set by losses of osteo-cartilagenous substances around the little bones, the finger- and toe-joints for example, the authors scanned a way different from that of amputation or arthrodesis: the functional rebuilding with the help of substitution grafts. An exploratory research conducted on 21 rabbits in Bordeaux in 1990 allowed to test the coupling of two bio-materials used in surgery here and now, a coupling which has not shown any side-effect and whose benefit is to obtain a non-deformable mass, colonizable by osteoblastic cells. The loss of articular substance suffered by a patient in his fingers in 1992 profited by this bone-rebuilding technique. The use of an external articulated stabilizer was an important provisional support during the colonization of the grafts by the osteoblasts. The difference of time in the osseus rebuilding between the rabbits on the one hand, and the human being on the other, is recorded.