Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation.

Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry

Realising stratified psychiatry using multidimensional signatures and trajectories

BACKGROUND: Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry. METHODS AND FINDINGS: To achieve a truly ‘stratified psychiatry’ we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia—conceptualised as a label for heterogeneous disorders—as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal. CONCLUSION: We describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

Universal ratios of critical amplitudes in the Potts model universality class

Monte Carlo (MC) simulations and series expansions (SE) data for the energy, specific heat, magnetization, and susceptibility of the three-state and four-state Potts model and Baxter-Wu model on the square lattice are analyzed in the vicinity of the critical point in order to estimate universal combinations of critical amplitudes. We also form effective ratios of the observables close to the critical point and analyze how they approach the universal critical-amplitude ratios. In particular, using the duality relation, we show analytically that for the Potts model with a number of states $q\le 4$, the effective ratio of the energy critical amplitudes always approaches unity linearly with respect to the reduced temperature. This fact leads to the prediction of relations among the amplitudes of correction-to-scaling terms of the specific heat in the low- and high-temperature phases. It is a common belief that the four-state Potts and the Baxter-Wu model belong to the same universality class. At the same time, the critical behavior of the four-state Potts model is modified by logarithmic corrections while that of the Baxter-Wu model is not. Numerical analysis shows that critical amplitude ratios are very close for both models and, therefore, gives support to the hypothesis that the critical behavior of both systems is described by the same renormalization group fixed point.Comment: Talk presented at CCP 2008, Ouro Preto, 5-9 August 200

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

2001 AAPP Monograph Series

The African American Professors Program (AAPP) at the University of South Carolina is pleased to produce this premier edition of its annual monograph series. It is fitting that the program assume a leadership role in promoting scholarly products that will prove to be useful in future research efforts by faculty and students in higher education. Scholars who have contributed manuscripts for this monograph are to be commended for adding this additional responsibility to their academic workload. Writing across disciplines adds to the intellectual diversity of these papers. From neophytes, relatively speaking, to an array of very experienced individuals, the chapters have been researched and, comprehensively, written. AAPP was created in 1997 under the leadership of Drs. Aretha B. Pigford and Leonard 0. Pellicer, Department of Educational Leadership and Policies. It was designed to address the underrepresentation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored by the University of South Carolina, the W. K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits students with bachelor\u27s, master\u27s, and doctoral degrees for disciplines in which African Americans, currently, are underrepresented. An important component of the program is the mentoring experience that is provided. Each student is assigned to a mentor professor who guides the student through a selected academic program and provides various learning experiences. When possible, the mentor serves as chair of the student\u27s doctoral committee. The mentor, also, provides opportunities for the student to team teach, conduct research, and co-author publications. Students have opportunities to attend committee, faculty, and professional meetings, as well as engage in a range of activities that characterize professional life in academia. Scholars enrolled in the program, also, are involved in programmatic and institutional workshops, independent research, and program development. The establishment or genesis of this monograph series is seen as responding to an opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, also, one that allows for the dissemination of AAPP products to a broader community. We hope that you, likewise, will read this premier monograph of the African American Professors Program with enthusiasm or enlightenment. John McFadden, Ph.D. The Benjamin Elijah Mays Professor Director, African American Professors Program University of South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1005/thumbnail.jp

Stimulating cognition in schizophrenia: A controlled pilot study of the effects of prefrontal transcranial direct current stimulation upon memory and learning

BACKGROUND: Schizophrenia is characterized by prominent cognitive deficits, impacting on memory and learning; these are strongly associated with the prefrontal cortex. OBJECTIVE/HYPOTHESIS: To combine two interventions, transcranial direct current stimulation (tDCS) over the prefrontal cortex and cognitive training, to examine change in cognitive performance in patients with schizophrenia. METHODS: A double blind, sham-controlled pilot study of 49 patients with schizophrenia, randomized into real or sham tDCS stimulation groups. Subjects participated in 4 days of cognitive training (days 1, 2, 14, 56) with tDCS applied at day-1 and day-14. The primary outcome measure was change in accuracy on working memory and implicit learning tasks from baseline. The secondary outcome measure was the generalization of learning to non-trained task, indexed by the CogState neuropsychological battery. Data analysis was conducted using multilevel modelling and multiple regressions. RESULTS: 24 participants were randomized to real tDCS and 25 to sham. The working memory task demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 (b = 0.68, CI 0.14-1.21; p = 0.044) and at day-56 (b = 0.71, 0.16-1.26; p = 0.044). There were no significant effects of tDCS on implicit learning. Trend evidence of generalization onto untrained tasks of attention and vigilance task (b = 0.40, 0.43-0.77; p = 0.058) was found. CONCLUSIONS: This is the first study to show a significant longer-term effect of tDCS on working memory in schizophrenia. Given the current lack of effective therapies for cognitive deficits, tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia