Predicting psychosis risk using a specific measure of cognitive control: a 12-month longitudinal study.

BACKGROUND: Identifying risk factors of individuals in a clinical-high-risk state for psychosis are vital to prevention and early intervention efforts. Among prodromal abnormalities, cognitive functioning has shown intermediate levels of impairment in CHR relative to first-episode psychosis and healthy controls, highlighting a potential role as a risk factor for transition to psychosis and other negative clinical outcomes. The current study used the AX-CPT, a brief 15-min computerized task, to determine whether cognitive control impairments in CHR at baseline could predict clinical status at 12-month follow-up. METHODS: Baseline AX-CPT data were obtained from 117 CHR individuals participating in two studies, the Early Detection, Intervention, and Prevention of Psychosis Program (EDIPPP) and the Understanding Early Psychosis Programs (EP) and used to predict clinical status at 12-month follow-up. At 12 months, 19 individuals converted to a first episode of psychosis (CHR-C), 52 remitted (CHR-R), and 46 had persistent sub-threshold symptoms (CHR-P). Binary logistic regression and multinomial logistic regression were used to test prediction models. RESULTS: Baseline AX-CPT performance (d-prime context) was less impaired in CHR-R compared to CHR-P and CHR-C patient groups. AX-CPT predictive validity was robust (0.723) for discriminating converters v. non-converters, and even greater (0.771) when predicting CHR three subgroups. CONCLUSIONS: These longitudinal outcome data indicate that cognitive control deficits as measured by AX-CPT d-prime context are a strong predictor of clinical outcome in CHR individuals. The AX-CPT is brief, easily implemented and cost-effective measure that may be valuable for large-scale prediction efforts.

Solid-State Emission from Mono- and Bichromophoric Boron Dipyrromethene (BODIPY) Derivatives and Comparison with Fluid Solution.

The syntheses and crystal structures of sterically crowded mono- and bichromophoric BODIPY-based dyes are reported. The "monomeric" compound is weakly fluorescent in the liquid phase due to fast internal conversion associated with rotation of aryl rings at the boron atom. The side-by-side "dimer" exhibits weak excitonic coupling between the dipyrrin units and is much more emissive in fluid solution. Solid samples of both molecular entities are strongly fluorescent under near-UV illumination. Thus, the mono-chromophore exhibits dual fluorescence from what appears to be a mixture of crystalline and possibly amorphous (or interfacial regions) distributions. The bi-chromophore packs in the crystal as pairs of chromophores with each unit being provided by a different molecule. This leads to excitonic splitting and the formation of a strong H-band in the absorption spectrum. Fluorescence occurs from the corresponding J-species and also from what appears to be an aggregated state associated with interfacial areas. Both bulk and interface-bound states show relatively long-lived fluorescence while the crystal structures indicate the likelihood for fast electronic energy migration between molecules.

Amphibious fish 'get a jump' on terrestrial locomotor performance after exercise training on land.

Many amphibious fishes rely on terrestrial locomotion to accomplish essential daily tasks, but it is unknown whether terrestrial exercise improves the locomotor performance of fishes on land. Thus, we tested the hypothesis that terrestrial exercise improves locomotion in amphibious fishes out of water as a result of skeletal muscle remodeling. We compared the jumping performance of Kryptolebias marmoratus before and after an exercise training regimen, and assessed the muscle phenotype of control and exercise-trained fish. We found that exercise-trained fish jumped 41% farther and 48% more times before reaching exhaustion. Furthermore, exercise training resulted in the hypertrophy of red muscle fibers, and an increase in red muscle capillarity and aerobic capacity. Lactate accumulation after jumping indicates that white muscle is also important in powering terrestrial jumps. Overall, skeletal muscle in K. marmoratus is highly responsive to terrestrial exercise, and muscle plasticity may assist in the effective exploitation of terrestrial habitats by amphibious fishes.

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY: Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.

Influence of Chain Length on the Structures and Dynamic Behavior of Alkyl-Tethered α,ω-Diphosphide Complexes of Lithium and Their Use in the Synthesis of P-Heterocyclic Stannylenes.

The alkyl-tethered α,ω-diphosphines (Dipp)PH(CH2) nPH(Dipp) ( n = 1 (3H), 2 (4H), 3 (5H), 4 (6H), and 5 (7H)) were prepared in good yield and characterized by multinuclear NMR spectroscopy [Dipp = 2,6- iPr2C6H3]. Treatment of 3H with 2 equiv of nBuLi and 2 equiv of TMEDA gives the diphosphide complex [CH2{P(Dipp)}2]Li2(TMEDA)2 (3Lia), which crystallizes as discrete monomers which do not exhibit temperature-dependent NMR behavior. Treatment of 4H-7H with 2 equiv of nBuLi in THF gives the diphosphides [[CH2{P(Dipp)}]2]2Li4(THF)2(OEt2)2 (4Li), [CH2{CH2P(Dipp)}2]Li2(THF)4 (5Li), [{CH2CH2P(Dipp)}2]Li2(THF)6 (6Li), and [CH2{CH2CH2P(Dipp)}2]2Li4(THF)6·PhMe (7Li) after crystallization. Compounds 4Li-7Li adopt either monomeric or dimeric structures in the solid state, depending on the length of the alkyl tether of the diphosphide ligand. In solution, compounds 4Li-7Li exhibit dynamic behavior: variable-temperature 31P{1H} and 7Li NMR spectroscopic studies indicate that this involves equilibria between monomeric and dimeric or higher oligomeric species with the nature of the equilibrium again depending on the length of the alkyl tether of the diphosphide ligand. The reactions between 3Li, 6Li, or 7Li and SnCl2 in THF give mixtures of products which could not be separated. In contrast, the reactions between 4Li or 5Li and 1 equiv of SnCl2 give the dimeric P-heterocyclic stannylenes [{CH2P(Dipp)}2Sn]2 (4Sn) and [CH2{CH2P(Dipp)}2Sn]2.1/2THF (5Sn), respectively. While compound 5Sn is isolated exclusively as the cis isomer, 4Sn is isolated as a mixture of cis and trans isomers in an approximate 5:1 ratio. The solid-state structures of trans-4Sn and cis-5Sn were obtained, and multinuclear NMR spectroscopy indicates that the dimeric structures of these compounds are maintained in solution. Compounds 4Sn and 5Sn represent the first P-heterocyclic stannylene dimers to be structurally characterized.

Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1, and MBJ-0035.

The madurastatins are pentapeptide siderophores originally described as containing an unusual salicylate-capped N-terminal aziridine ring. Isolation of madurastatin C1 (1) (also designated MBJ-0034), from Actinomadura sp. DEM31376 (itself isolated from a deep sea sediment), prompted structural reevaluation of the madurastatin siderophores, in line with the recent work of Thorson and Shaaban. NMR spectroscopy in combination with partial synthesis allowed confirmation of the structure of madurastatin C1 (1) as containing an N-terminal 2-(2-hydroxyphenyl)oxazoline in place of the originally postulated aziridine, while absolute stereochemistry was determined via Harada's advanced Marfey's method. Therefore, this work further supports Thorson and Shaaban's proposed structural revision of the madurastatin class of siderophores (madurastatins A1 (2), B1 (3), C1 (1), and MBJ-0036 (4)) as N-terminal 2-(2-hydroxyphenyl)oxazolines.

Family Interventions for Schizophrenia and the Psychoses: A Review.

Family psychoeducation as a treatment for schizophrenia was developed 40 years ago almost simultaneously and independently by investigators who at the time were not family therapists. Although the original goal was to decrease high expressed emotion as a means of preventing relapse, later variations have gone beyond to focus on social and role functioning and family well-being. Explicitly disavowing the earlier assumptions that family pathology caused relapse and deterioration, family psychoeducation seeks to engage family members as more sophisticated partners, complementing interventions by clinicians with specialized interactions and coping skills that counter the neurologic deficits inherent to the disorder. It has proved to be one of the most consistently effective treatments available. Reports on outcome studies now number more than 100, while meta-analyses put relapse rate reduction at 50-60% over treatment as usual. The most recent application in first episode and prodromal psychosis, combined with other evidence-based interventions, is yielding perhaps the most promising results yet achieved-substantial return of functioning and avoidance of psychosis altogether. Reviewed here are its scientific, theoretical, and clinical sources, a description of the most commonly applied version-the multifamily group format, selected clinical trials spanning those four decades, international and ethnic adaptations, and studies on mechanisms of efficacy.

Recreational cannabis use over time in individuals at clinical high risk for psychosis: Lack of associations with symptom, neurocognitive, functioning, and treatment patterns.

Recreational cannabis use has recently gained considerable interest as an environmental risk factor that triggers the onset of psychosis. To date, however, the evidence that cannabis is associated with negative outcomes in individuals at clinical high risk (CHR) for psychosis is inconsistent. The present study tracked cannabis usage over a 2-year period and examined its associations with clinical and neurocognitive outcomes, along with medication rates. CHR youth who continuously used cannabis had higher neurocognition and social functioning over time, and decreased medication usage, relative to non-users. Surprisingly, clinical symptoms improved over time despite the medication decreases.

The association between mental health stigma and face emotion recognition in individuals at risk for psychosis.

Self-stigma has been associated with reduced accuracy of face emotion recognition in individuals at clinical high risk for psychosis (CHR). Stigma may also relate to slowing of performance during cognitive tasks for which a negative stereotype is relevant. This study aimed to investigate the association of mental illness stigma with face emotion recognition among CHR individuals. Participants were 143 CHR individuals identified using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Face emotion recognition was assessed using the Penn Emotion Recognition Task (ER-40). Stigma was assessed using discrimination, stereotype awareness, and stereotype agreement subscales of the Mental Health Attitudes Interview for CHR. We tested associations of ER-40 accuracy and response times with these stigma variables, including the role of clinical and demographic factors. Racial/ethnic minoritized participants had higher attenuated positive symptoms than non-minoritized participants. Longer ER-40 response times were correlated with greater stereotype agreement (r=.17, p=.045) and discrimination (r=.22, p=.012). A regression model predicting ER-40 response times revealed an interaction of stereotype agreement with minoritized status (p=.008), with slower response times for minoritized participants as stereotype agreement increased. Greater disorganized symptoms and male gender also predicted longer response times. ER-40 accuracy was not associated with stigma. Overall, minoritized CHR individuals with greater internalized stigma took longer to identify face emotions. Future research is needed to assess whether slower response times are specific to social cues, and if internalized stigma interferes with performance in real-world social situations. Reducing stigma may be an important target for interventions that aim to improve social skills.

Experimental study of hydrogen bonding potentially stabilizing the 5'-deoxyadenosyl radical from coenzyme†B12.

Coenzyme B(12) can assist radical enzymes that accomplish the vicinal interchange of a hydrogen atom with a functional group. It has been proposed that the Co-C bond homolysis of coenzyme B(12) to cob(II)alamin and the 5'-deoxyadenosyl radical is aided by hydrogen bonding of the corrin C19-H to the 3'-O of the ribose moiety of the incipient 5'-deoxyadenosyl radical, which is stabilized by 30 kJ mol(-1) (B. Durbeej et al., Chem. Eur. J. 2009, 15, 8578-8585). The diastereoisomers (R)- and (S)-2,3-dihydroxypropylcobalamin were used as models for coenzyme B(12). A downfield shift of the NMR signal for the C19-H proton was observed for the (R)-isomer (δ=4.45 versus 4.01 ppm for the (S)-isomer) and can be ascribed to an intramolecular hydrogen bond between the C19-H and the oxygen of CHOH. Crystal structures of (R)- and (S)-2,3-dihydroxypropylcobalamin showed C19-H⋅⋅⋅O distances of 3.214(7) Š(R-isomer) and 3.281(11) Š(S-isomer), which suggest weak hydrogen-bond interactions (-ΔG<6 kJ mol(-1)) between the CHOH of the dihydroxypropyl ligand and the C19-H. Exchange of the C19-H, which is dependent on the cobalt redox state, was investigated with cob(I)alamin, cob(II)alamin, and cob(III)alamin by using NMR spectroscopy to monitor the uptake of deuterium from deuterated water in the pH range 3-11. No exchange was found for any of the cobalt oxidation states. 3',5'-Dideoxyadenosylcobalamin, but not the 2',5'-isomer, was found to act as a coenzyme for glutamate mutase, with a 15-fold lower k(cat)/K(M) than 5'-deoxyadenosylcobalamin. This indicates that stabilization of the 5'-deoxyadenosyl radical by a hydrogen bond that involves the C19-H and the 3'-OH group of the cofactor is, at most, 7 kJ mol(-1) (-ΔG). Examination of the crystal structure of glutamate mutase revealed additional stabilizing factors: hydrogen bonds between both the 2'-OH and 3'-OH groups and glutamate 330. The actual strength of a hydrogen bond between the C19-H and the 3'-O of the ribose moiety of the 5'-deoxyadenosyl group is concluded not to exceed 6 kJ mol(-1) (-ΔG).

Describing and Characterizing the Literature Regarding Umbilical Health in Intensively Raised Cattle: A Scoping Review.

The objective of this scoping review was to describe and characterize the existing literature regarding umbilical health and identify gaps in knowledge. Six databases were searched for studies examining umbilical health in an intensively raised cattle population. There were 4249 articles initially identified; from these, 723 full text articles were then screened, with 150 articles included in the review. Studies were conducted in the USA (n = 41), Brazil (n = 24), Canada (n = 13), UK (n = 10), and 37 additional countries. Seventeen were classified as descriptive, 24 were clinical trials, and 109 were analytical observational studies. Umbilical outcomes evaluated in descriptive studies were infection (n = 11), parasitic infection (n = 5), and hernias (n = 2). Of the clinical trials, only one examined treatment of navel infections; the remainder evaluated preventative management factors for navel health outcomes (including infections (n = 17), myiasis (n = 3), measurements (n = 5), hernias (n = 1), and edema (n = 1)). Analytical observational studies examined risk factors for umbilical health (n = 60) and umbilical health as a risk factor (n = 60). Studies examining risk factors for umbilical health included navel health outcomes of infections (n = 28; 11 of which were not further defined), hernias (n = 8), scoring the navel sheath/flap size (n = 16), myiasis (n = 2), and measurements (n = 6). Studies examining umbilical health as a risk factor defined these risk factors as infection (n = 39; of which 13 were not further defined), hernias (n = 8; of which 4 were not further defined), navel dipping (n = 12), navel/sheath scores as part of conformation classification for breeding (n = 2), measurements (n = 3), and umbilical cord drying times (n = 2). This review highlights the areas in need of future umbilical health research such as clinical trials evaluating the efficacy of different treatments for umbilical infection. It also emphasizes the importance for future studies to clearly define umbilical health outcomes of interest, and consider standardization of these measures, including time at risk.

Multifamily group psychoeducation and cognitive remediation for first-episode psychosis: a randomized controlled trial.

BACKGROUND: Multifamily group psychoeducation (MFG) has been shown to reduce relapse rates among individuals with first-episode psychosis. However, given the cognitive demands associated with participating in this intervention (e.g., learning and applying a structured problem-solving activity), the cognitive deficits that accompany psychotic disorders may limit the ability of certain individuals to benefit from this intervention. Thus, the goal of this study is to examine whether individuals with first-episode psychosis who participate simultaneously in MFG and cognitive remediation--an intervention shown to improve cognitive functioning among individuals with psychotic disorders--will be less likely to experience a relapse than individuals who participate in MFG alone. METHODS/DESIGN: Forty individuals with first-episode psychosis and their caregiving relative will be recruited to participate in this study. Individuals with first-episode psychosis will be randomized to one of two conditions: (i) MFG with concurrent participation in cognitive remediation or (ii) MFG alone. The primary outcome for this study is relapse of psychotic symptoms. We will also examine secondary outcomes among both individuals with first-episode psychosis (i.e., social and vocational functioning, health-related quality of life, service utilization, independent living status, and cognitive functioning) and their caregiving relatives (i.e., caregiver burden, anxiety, and depression) DISCUSSION: Cognitive remediation offers the possibility of ameliorating a specific deficit (i.e., deficits in cognitive functioning) that often accompanies psychotic symptoms and may restrict the magnitude of the clinical benefits derived from MFG. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01196286.

Emotional and stigma-related experiences relative to being told one is at risk for psychosis.

OBJECTIVE: Despite the appeal of early intervention in psychosis, there is concern that identifying youth as having high psychosis risk (PR) may trigger stigma. This study employed a pre-post design to measure change in PR participants' emotions about PR upon being told of their PR status and according to whether this was the first time receiving this information. METHODS: Participants (n = 54) identified as at PR via structured interview rated their emotions about PR before and after being told they were at PR. Qualitative analyses explored the valence of participant reflections on being given this information. RESULTS: Participants reported significantly less negative emotion after being told of their PR status (p < .001), regardless of whether they were hearing this for the first time (p = .72). There was no change in positive emotions or the predominant belief that they should keep their PR status private. Most participants commented positively about the process of feedback but negatively about its impact on their self-perceptions and/or expectations of others' perceptions of them. CONCLUSION: This is the first study to collect pre-post data related to being told one is at PR and to examine quantitative and qualitative responses across and within individuals. For a majority of participants, clinical feedback stimulated negative stereotypes even as it relieved some distress. To actively address internalized stigma, clinicians providing feedback to PR youth must attend to the positive and negative impacts on how youth think about themselves as well as how they feel.

Self-assembly of a bis(adeninyl)-Cu(I) complex: a cationic nucleobase duplex mimic.

The tetrahedral bis(adeninyl)-Cu(I) complex, , self-associates in polar solvent through complementary hydrogen-bonding interactions and appears to mimic the natural assembly of duplex DNA.

Partnering with families: multiple family group psychoeducation for schizophrenia.

Family psychoeducation (FPE) is one of six evidence-based practices endorsed by the Center for Mental Health Services for individuals suffering from chronic mental illnesses. Multiple family group psychoeducation (MFG) has been shown to be an effective component of FPE in reducing symptom relapses and rehospitalizations for individuals with schizophrenia. It is especially effective when family members participate on a consistent basis, which allows them to increase their understanding of the biology of the disorder, learn ways to be supportive, reduce stress in the environment and in their own lives, and develop a broader social network. When used in conjunction with medication, MFG can help an individual with schizophrenia progress towards the rehabilitation phase of recovery. A case illustration describes the engagement of a chronically ill, mid-thirties male in MFG and how his family's participation for 2 years benefits all members, in spite of the longevity of his illness.

Sensory characteristics of youth at clinical high risk for psychosis.

AIM: To identify and compare the sensory characteristics of young people at clinical high risk (CHR) for psychosis to those of peers at clinical low risk (CLR), and to national normative data. CHR and CLR participants were recruited from 6 US regions. METHOD: A descriptive cohort design was used to analyse baseline data collected as part of the Early Detection and Intervention for the Prevention of Psychosis Program (EDIPPP). Raw scores on the Adolescent/Adult Sensory Profile (AASP) were analysed for 205 young people with CHR and 87 with CLR in 2 age groups: 12 to 17 years (N = 203) and 18 to 25 years (N = 89). ANOVA procedures were used to determine whether differences in AASP scores existed across CLR, CHR, and normative groups by age group. RESULTS: CHR participants differed significantly from the normative group for all 4 AASP quadrant scores (Low Registration, Sensory Seeking, Sensory Sensitivity and Sensory Avoiding) in both age groups. CLR participants were similar to norms, except for Sensory Seeking scores that were significantly lower than norms in both age ranges. CONCLUSION: Young people with CHR demonstrate active avoidance, heightened sensitivity, reduced seeking, and reduced registration of sensations in everyday life compared to typical peers. This pattern of differences may be a valuable marker for identifying individuals who are at high risk for developing a psychotic illness, and may also inform interventions designed to prevent or minimize the illness process and accompanying dysfunction.

Impact of "psychosis risk" identification: Examining predictors of how youth view themselves.

BACKGROUND: Identifying young people as at clinical high-risk (CHR) for psychosis affords opportunities for intervention to possibly prevent psychosis onset. Yet such CHR identification could plausibly increase stigma. We do not know whether these youth already perceive themselves to be at psychosis-risk (PR) or how their being told they are at PR might impact how they think about themselves. METHODS: 148 CHR youth were asked about labels they had been given by others (labeling by others) or with which they personally identified (self-labeling). They were then asked which had the greatest impact on how they thought about themselves. We evaluated whether being told vs. thinking they were at PR had stronger effects. FINDINGS: The majority identified nonpsychotic disorders rather than PR labels as having the greatest impact on sense of self (67.6% vs. 27.7%). However, participants who identified themselves as at PR had an 8.8 (95% CI = 2.0-39.1) increase in the odds of the PR label having the greatest impact (p < 0.01). Additionally, having been told by others that they were at PR was associated with a 4.0 increase in odds (95% CI = 1.1-15.0) that the PR label had the most impact (p < 0.05). INTERPRETATION: Nonpsychotic disorder labels appear to have a greater impact on CHR youth than psychosis-risk labels. However, thinking they are at PR, and, secondarily, being told they are at PR, appears to increase the relative impact of the PR label. Understanding self- and other-labeling may be important to how young people think of themselves, and may inform early intervention strategies.

Baseline psychopathology and relationship to longitudinal functional outcome in attenuated and early first episode psychosis.

BACKGROUND: As efforts intensify to intervene early among those at risk for psychosis, examination of the relationship between presenting psychopathology and long-term functional outcome may guide treatment decision-making and offer a means to prevent or reduce chronic disability. METHODS: Data were collected through the Early Detection and Intervention for the Prevention of Psychosis Program (EDIPPP), a multisite national trial testing the efficacy of an early intervention for youth at risk of developing psychosis. Participants were followed prospectively and completed comprehensive evaluations at 6, 12, and 24 months, including the Structured Interview for Prodromal Syndromes (SIPS) and the Global Social and Role Functioning Scales. The present analyses included 327 participants and examined the relationships between baseline symptoms and longitudinal global social and role functioning using a linear mixed modeling approach. RESULTS: Higher baseline negative symptoms and deteriorated thought process predicted worse social and role functioning in the follow-up period. The effect of negative symptoms on social functioning, however, was moderated by positive symptoms, and the relationship between positive symptoms and social functioning changed over time. Baseline positive symptoms, distress, and level of symptom severity were not predictors of either social or role functioning. CONCLUSIONS: Baseline negative symptoms and thought disorder appear to predict functional outcome for up to two years among adolescents and young adults at risk for psychosis. Developing effective interventions to target these symptoms may be critical to promote functional recovery among those experiencing attenuated symptoms or a first episode of psychosis.

Pi-interaction tuning of the active site properties of metalloproteins.

The influence of pi-interactions with a His ligand have been investigated in a family of copper-containing redox metalloproteins. The Met16Phe and Met16Trp pseudoazurin, and Leu12Phe spinach and Leu14Phe Phormidium laminosum plastocyanin variants possess active-site pi-contacts between the introduced residue and His81 and His87/92 respectively. The striking overlap of the side chain of Phe16 in the Met16Phe variant and that of Met16 in wild type pseudoazurin identifies that this position provides an important second coordination sphere interaction in both cases. His-ligand protonation and dissociation from Cu(I) occurs in the wild type proteins resulting in diminished redox activity, providing a [H(+)]-driven switch for regulating electron transfer. The introduced pi-interaction has opposing effects on the pKa for the His ligand in pseudoazurin and plastocyanin due to subtle differences in the pi-contact, stabilizing the coordinated form of pseudoazurin whereas in plastocyanin protonation and dissociation is favored. Replacement of Pro36, a residue that has been suggested to facilitate structural changes upon His ligand protonation, with a Gly, has little effect on the pKa of His87 in spinach plastocyanin. The mutations at Met16 have a significant influence on the reduction potential of pseudoazurin. Electron self-exchange is enhanced, whereas association with the physiological partner, nitrite reductase, is only affected by the Met16Phe mutation, but kcat is halved in both the Met16Phe and Met16Trp variants. Protonation of the His ligand is the feature most affected by the introduction of a pi-interaction.

The employment intervention demonstration program: major findings and policy implications.

This article summarizes the published results of the Employment Intervention Demonstration Program (EIDP), a federally-funded, multi-site study examining the effectiveness of supported employment programs for 1273 unemployed individuals with psychiatric disabilities in the U.S. Findings confirm the effectiveness of supported employment across different models, program locations, and participant populations. The study's results are discussed in the context of public policies designed to encourage return to work for those with a severe mental illness.