APOBEC3G protects the genome of human cultured cells and mice from radiation-induced damage.

Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

APOBEC3G rescues cells from the deleterious effects of DNA damage.

Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (hA3G), a member of the APOBEC family, was described as an anti-HIV-1 restriction factor, deaminating reverse transcripts of the HIV-1 genome. Several types of cancer cells that express high levels of A3G, such as diffuse large B-cell lymphoma cells and glioblastomas, show enhanced cell survival after ionizing radiation and chemotherapy treatments. Previously, we showed that hA3G promotes (DNA) double-strand breaks repair in cultured cells and rescues transgenic mice from a lethal dose of ionizing radiation. Here, we show that A3G rescues cells from the detrimental effects of DNA damage induced by ultraviolet irradiation and by combined bromodeoxyuridine and ultraviolet treatments. The combined treatments stimulate the synthesis of cellular proteins, which are exclusively associated with A3G expression. These proteins participate mainly in nucleotide excision repair and homologous recombination DNA repair pathways. Our results implicate A3G inhibition as a potential strategy for increasing tumor cell sensitivity to genotoxic treatments.

A mutation in POLR3E impairs antiviral immune response and RNA polymerase III.

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Occupation-focused intervention for in-patient mental health settings: Pilot study of effectiveness.

PURPOSE: Participation in meaningful occupation is associated with recovery in serious mental illnesses, however, few evidence-based, occupation-focused interventions for hospital settings exist. This study investigated the effectiveness of "Occupational Connections" (OC), a manualized, short-term, group intervention, addressing issues in daily-life occupations' participation and functioning of people with serious mental illness as early as during hospitalization. METHODS: Thirty-three inpatients with schizophrenia completed single-blind, pre-post study procedures (up to 10 weeks) in two groups: OC group intervention and open leisure activity group (control condition), in addition to treatment as usual. They were assessed for occupation and participation dimensions, perceptions of services as recovery-oriented, comprehensive cognitive functioning and schizophrenia symptoms. The sampling was convenience with sequential group allocation. RESULTS: Improvements were found in the study group in the following measurements: intention to participate in daily activities (t(15) = -2.62, p < .05), participation diversity (t(15) = -2.11, p < .05), experience the recovery orientation of the service (t(15) = -3.15, p < .01), functional capacity (t(15) = -3.44, p < .01), cognitive abilities of language understanding, memory and shifting (-4.5

Nanocapsules embedded in microparticles for enhanced oral bioavailability and efficacy of Lopinavir as an anti-AIDS drug.

Lopinavir (LPV), an efficient drug for HIV infection treatment, was incorporated into biodegradable PLGA nanocapsules (NCs) embedded in microparticles (MCPs) using the spray-drying technique in an attempt to bypass the P-gp efflux and protect the drug from CYP3A pre-systemic metabolism without ritonavir (RTV). SEM observations confirmed the formation of NCs and their entrapment in the MCPs. LPV-loaded NCs and free LPV were released from the MCPs at pH of 7.4 as evidenced by in vitro release studies. Results obtained from rat studies showed a two-fold higher bioavailability of LPV following oral administration of the optimal formulation than Kaletra®, the marketed drug, showing that when properly entrapped, LPV can be effectively protected from CYP degradation in the gut as well as from the liver following systemic absorption. It was also shown that serum derived from rats following LPV oral administration in two formulations and Kaletra® significantly decreased the multiplication of HIV-1 in cultured SupT1 cells. Furthermore, the LPV formulations markedly restricted the titre of infectious HIV-1 production compared with Kaletra® confirming the improved antiviral activity of LPV delivered in the rat blood circulation by the nanocapsules embedded in microparticle formulations.

Social affective context reveals altered network dynamics in schizophrenia patients.

Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social-affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks' NCI dynamic during the social-affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social-affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another's' distress may underlie social-affective deficits in schizophrenia.

Prediction of the intensity and diversity of day-to-day activities among people with schizophrenia using parameters obtained during acute hospitalization.

PURPOSE: Participation in day-to-day activities of people with schizophrenia is restricted, causing concern to them, their families, service providers and the communities at large. Participation is a significant component of health and recovery; however, factors predicting participation are still not well established. This study examines whether the parameters obtained during acute hospitalization can predict the intensity and diversity of participation in day-to-day activities six months after discharge. METHOD: In-patients with chronic schizophrenia (N = 104) were enrolled into the study and assessed for cognitive functioning, functional capacity in instrumental activities of daily living (IADL), and symptoms. Six months after discharge, the intensity and diversity of participation in day-to-day activities were evaluated (N = 70). RESULTS: Multiple correlations were found between parameters obtained during hospitalization and participation diversity, but not participation intensity. The model that is better suited to the prediction of participation diversity contains cognitive ability of construction, negative symptoms and number of previous hospitalizations. The total explained variance is 37.8% (F3,66 = 14.99, p < 0.001). CONCLUSIONS: This study provides evidence for ecological validity of the in-patient evaluation process for the prediction of participation diversity in day-to-day activities six months after discharge. Participation diversity is best predicted through a set of factors reflecting personal and environmental indicators. Implications for rehabilitation Results of in-patient evaluations can predict the diversity of participation in day-to-day activities six months after discharge. Higher prediction of participation diversity is obtained using a holistic evaluation model that includes assessments for cognitive abilities, negative symptoms severity and number of hospitalizations.

[BIPOLAR DISORDER AS A MULTI-SYSTEM ILLNESS].

INTRODUCTION: Bipolar disorder is a chronic condition, characterized by high distress in patients and high suicide rates (30%). Most patients suffer from medical and other psychiatric comorbidities, which worsen the psychiatric symptoms and decrease the likelihood of remission. More than 70% of bipolar patients have cardio-metabolic symptoms, with higher rates compared to other psychiatric disorders. Cardiovascular disease is the major cause of high mortality rates in these patients, with 1.5-2 fold increased risk of mortality, compared to the general population without psychiatric symptoms. The rates of cardiovascular risk factors and their resulting increased mortality rates are similar to those found in schizophrenia. In addition to cardio-metabolic conditions, 50% of patients with bipolar disorder suffer from other medical symptoms, which are also associated with worse outcomes. Therefore, the current perspective is that bipolar disorder is not only a psychiatric disorder, but rather a multi-system illness, affecting the entire body. The optimal treatment for these patients should include diagnosis, monitoring and treatment of both psychiatric and physical symptoms, which would improve their prognosis.

[NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS].

INTRODUCTION: This review deals with the neuropsychiatric disorders resulting from systemic lupus erythematosus (SLE). SLE is a chronic autoimmune disease that impacts all systems in the human body, including the central nervous system. Neuropsychiatric symptoms in SLE are a common complication of the disease. This complication has significant implications for the severity of the illness. In most cases no thorough psychiatric assessment is performed during initial evaluation of the disease and no protocol or clear guidelines for treating the psychiatric symptoms in SLE are available. Early diagnosis of the psychiatric symptoms in SLE is critical since absence of treatment may result in severe psychiatric complications. Clinical pharmacological studies are needed in order to develop guidelines for treating psychiatric symptoms in SLE.

Description of and Preliminary Findings for Occupational Connections, an Intervention for Inpatient Psychiatry Settings.

People with mental health conditions (MHCs) frequently experience participation and functional restrictions. Today, hospitals still serve a significant number of people with MHCs. However, there is little evidence for occupation-oriented interventions to support participation, health, and well-being in these hospital settings. This article describes a newly developed, short-term, structured intervention for the inpatient setting, Occupational Connections (OC), that focuses on promoting everyday functions and participation in daily life and presents preliminary findings for its effectiveness. Ten people with schizophrenia participated in the program during their stay in acute open inpatient units and completed evaluations both pre- and postintervention. Statistics for a small-sample study design were applied to investigate OC's impact. The results showed OC's contribution to participation dimensions, functional capacity, cognitive functioning, and reduction in schizophrenia symptoms. On the basis of this pilot study's results, extended research is now being conducted to strengthen the evidence for OC's effectiveness.

The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical.

HIV-1 integrase (IN) catalyzes viral DNA integration into the host genome and facilitates multifunctional steps including virus particle maturation. Competency of IN to form multimeric assemblies is functionally critical, presenting an approach for anti-HIV strategies. Multimerization of IN depends on interactions between the distinct subunit domains and among the flanking protomers. Here, we elucidate an overlooked docking cleft of IN core domain that anchors the N-terminal helix-turn-helix (HTH) motif in a highly preserved and functionally critical configuration. Crystallographic structure of IN core domain in complex with Fab specifically targeting this cleft reveals a steric overlap that would inhibit HTH-docking, C-terminal domain contacts, DNA binding, and subsequent multimerization. While Fab inhibits in vitro IN integration activity, in vivo it abolishes virus particle production by specifically associating with preprocessed IN within Gag-Pol and interfering with early cytosolic Gag/Gag-Pol assemblies. The HTH-docking cleft may offer a fresh hotspot for future anti-HIV intervention strategies.

Participation in daily life of people with schizophrenia in comparison to the general population.

BACKGROUND: Participation in occupations is a basic human right. Although people with schizophrenia commonly experience restrictions in participation, there is a paucity of research in this area. PURPOSE: This study aimed to compare the participation patterns of people with schizophrenia to people without mental illness (control group). METHOD: A total of 140 people of similar age and sex completed the Adults Subjective Assessment of Participation and provided demographic and health-related data. FINDINGS: People with schizophrenia tend to participate in fewer activities and to participate alone. However, they participate with similar intensity as those in the control group. IMPLICATIONS: The participation patterns of people with schizophrenia are both unique and similar to those of the general population. The differences in participation raise concerns due to signs of restriction and social exclusion. However, it appears that people with schizophrenia benefit from occupation and community-based services that promote and support participation with others in diverse activities.

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

OBJECTIVE: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). METHODS: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. RESULTS: Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. CONCLUSION: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

Inhibition of APOBEC3G activity impedes double-stranded DNA repair.

The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in double-stranded DNA damage, such as ionizing radiation and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases the sensitivity of lymphoma cells to ionizing radiation. In the current study, we show that additional peptides derived from Vif, A3G, and APOBEC3F, which contain the LYYF motif, inhibit deamination activity. Each residue in the Vif25-39 sequence moderately contributes to the inhibitory effect, whereas replacing a single residue in the LYYF motif completely abrogates inhibition of deamination. Treatment of A3G-expressing lymphoma cells exposed to ionizing radiation with the new inhibitory peptides reduces double-strand break repair after irradiation. Incubation of cultured irradiated lymphoma cells with peptides that inhibit double-strand break repair halts their propagation. These results suggest that A3G may be a potential therapeutic target that is amenable to peptide and peptidomimetic inhibition.

Factors discriminating employment status following in-patient evaluation among persons with schizophrenia.

BACKGROUND: Employment is a key element in recovery from schizophrenia. Yet 60%-80% of people with schizophrenia are not involved in work occupations. Factors influencing employment were explored mostly in community settings, while the recovery process begins already during hospitalization. OBJECTIVE: The aim of the study was to investigate parameters that can distinguish during hospitalization between people with schizophrenia who will work in competitive employment, in sheltered employment or will not work after discharge. METHODS: The research followed 104 participants from acute hospitalization to the community, six months after discharge, to obtain employment related data. The participants' cognitive abilities, schizophrenia symptoms, and functional capacity were evaluated during hospitalization. In addition, demography and illness related factors were collected. RESULTS: The results indicate that persons with different employment statuses varied in several parameters during hospitalization. However, the most effective discriminant model includes negative symptoms, functional capacity measure and the number of hospitalizations. CONCLUSIONS: The study suggests that people with different employment statuses have unique characteristics already during hospitalization. In the future, appropriate rehabilitation programs may be suggested to each group based on these characteristics to promote employment among people with schizophrenia and contribute to recovery.

Ability to use the wait-and-see strategy in pathological gamblers.

Pathological gamblers (PGs) perform differently on neurocognitive tests than do healthy controls (HC). The aim of this study was to assess "waiting ability" - a major components of inhibition control-using a modified Stop Signal Task (SST) in a population of male PGs (N=55), and HCs (N=53). Results indicated no differences between PGs and HCs in reaction times, intra-individual response variability, or number of false alarms and misses. In conclusion, PGs were not impaired in their ability to manipulate their on-line response strategy during the experimental task and were instead able to change their strategy to decrease the number of false alarms. However, much more empirical and theoretical work needs to be carried out in order to understand the key neural basis of impulsivity among PGs.

Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead.

Chirality is an important aspect in many pharmacological processes including drug transport and metabolism. The current investigation examined the stereospecific transport and entry inhibitory activity of four diastereomers derived from a small (macrocyclic) molecule that has two chiral centers. These molecules were designed to mimic the interaction between CD4 and gp120 site of HIV-1 and thereby to function as entry inhibitor(s). Intestinal permeability was assessed by ex-vivo model using excised rat intestine mounted in side-by-side diffusion chambers. The entry inhibitory activity was monitored using indicator HeLa-CD4-LTR-beta-gal cells (MAGI assay). The (S/S) diastereomer, named CG-1, exhibited superiority in both unrelated tested biological processes: (I) high transport through the intestine and (II) entry inhibition activity (in the low µM range). The permeability screening revealed a unique transporter-mediated absorption pathway of CG-1, suggesting a significant role of the molecule's conformation on the mechanism of intestinal absorption. Here we highlight that only the S,S enantiomer (CG-1) has both (I) promising anti HIV-1 entry inhibitory properties and (II) high transporter mediated intestinal permeability. Hence we suggest preference in pharmacological processes to the S,S conformation. This report augments the knowledge regarding stereoselectivity in receptor mediated and protein-protein interaction processes.

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS: A Brief Report.

BACKGROUND: Deep transcranial magnetic stimulation (dTMS) is effective in treatment of Major Depressive Disorder (MDD), and in re-treatment in case of relapse. Our study evaluates the long-term durability of dTMS in MDD. METHOD: Seventeen patients that responded to dTMS treatment evaluated. Follow-up period was 9.3 months. Patients were considered as relapsed if: HDRS (Hamilton Depression Rating Scale) score was 16 points or more, in case of change in antidepressants, hospitalization due to exacerbation, referral to ECT. RESULTS: Six months after last treatment three patients relapsed (17.6%). During the follow-up of 9.3 months, nine relapsed. Relapse rate was 5.6 per 100 person-months. Patients continued to improve in HDRS following the treatment. We have found number of treatment sessions, stimulation, age, age of depressive disorder onset, length of depressive episode prior to the first treatment, as well as number of depressive episodes to have no predictive value regarding propensity to relapse in these patients. LIMITATIONS: The study's main limitations are the relatively small sample size, patients differing in follow-up periods and the lack of a control group. CONCLUSION: Relapse rates after dTMS are comparable to pharmacotherapy and ECT.

From hospital admission to independent living: is prediction possible?

An integral component of recovery from mental illness is being able to engage in everyday activities. This ability is often restricted among people with schizophrenia. Although functional deficits are addressed during hospitalization, the ability to predict daily functioning based on information gathered during hospitalization has not been well established. This study examines whether measurements completed during hospitalization can be useful for predicting independent living within the community. Inpatients with schizophrenia (N=104) were enrolled in the study and assessed for cognitive functioning, functional capacity and symptoms. They were approached again 6 months after discharge to evaluate their functioning with respect to everyday life Instrumental Activities of Daily Living (IADL) and Activities of Daily Living (ADL). Functional capacity during hospitalization predicted 26.8% of ADL functioning and 38.8% of IADL functioning. ADL was best predicted by the severity of negative symptoms, cognitive functioning, and the number of hospitalizations (51.2%), while IADL was best predicted by functional capacity, cognition, and number of hospitalizations (60.1%). This study provides evidence that evaluations during hospitalization can be effective, and demonstrates the advantage of a holistic approach in predicting daily functioning. When a holistic approach is not practical, a functional capacity measurement may serve as an effective predictor.

Mortality Caused by Bath Exposure of Zebrafish (Danio rerio) Larvae to Nervous Necrosis Virus Is Limited to the Fourth Day Postfertilization.

Nervous necrosis virus (NNV) is a member of the Betanodavirus genus that causes fatal diseases in over 40 species of fish worldwide. Mortality among NNV-infected fish larvae is almost 100%. In order to elucidate the mechanisms responsible for the susceptibility of fish larvae to NNV, we exposed zebrafish larvae to NNV by bath immersion at 2, 4, 6, and 8 days postfertilization (dpf). Here, we demonstrate that developing zebrafish embryos are resistant to NNV at 2 dpf due to the protection afforded by the egg chorion and, to a lesser extent, by the perivitelline fluid. The zebrafish larvae succumbed to NNV infection during a narrow time window around the 4th dpf, while 6- and 8-day-old larvae were much less sensitive, with mortalities of 24% and 28%, respectively.