Peroxisome compartmentalization of a toxic enzyme improves alkaloid production.

Eukaryotic cells compartmentalize metabolic pathways in organelles to achieve optimal reaction conditions and avoid crosstalk with cytosolic factors. We found that cytosolic expression of norcoclaurine synthase (NCS), the enzyme that catalyzes the first committed reaction in benzylisoquinoline alkaloid biosynthesis, is toxic in Saccharomyces cerevisiae and, consequently, restricts (S)-reticuline production. We developed a compartmentalization strategy that alleviates NCS toxicity while promoting increased (S)-reticuline titer.

DropSynth 2.0: high-fidelity multiplexed gene synthesis in emulsions.

Multiplexed assays allow functional testing of large synthetic libraries of genetic elements, but are limited by the designability, length, fidelity and scale of the input DNA. Here, we improve DropSynth, a low-cost, multiplexed method that builds gene libraries by compartmentalizing and assembling microarray-derived oligonucleotides in vortexed emulsions. By optimizing enzyme choice, adding enzymatic error correction and increasing scale, we show that DropSynth can build thousands of gene-length fragments at >20% fidelity.

Publisher Correction: Modular and tunable biological feedback control using a de novo protein switch.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

De novo design of bioactive protein switches.

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix 'cage' with a single interface that can interact either intramolecularly with a terminal 'latch' helix or intermolecularly with a peptide 'key'.

Modular and tunable biological feedback control using a de novo protein switch.

De novo-designed proteins hold great promise as building blocks for synthetic circuits, and can complement the use of engineered variants of natural proteins. One such designer protein-degronLOCKR, which is based on 'latching orthogonal cage-key proteins' (LOCKR) technology-is a switch that degrades a protein of interest in vivo upon induction by a genetically encoded small peptide. Here we leverage the plug-and-play nature of degronLOCKR to implement feedback control of endogenous signalling pathways and synthetic gene circuits.

The effects of childhood maltreatment on brain structure, function and connectivity.

Maltreatment-related childhood adversity is the leading preventable risk factor for mental illness and substance abuse. Although the association between maltreatment and psychopathology is compelling, there is a pressing need to understand how maltreatment increases the risk of psychiatric disorders. Emerging evidence suggests that maltreatment alters trajectories of brain development to affect sensory systems, network architecture and circuits involved in threat detection, emotional regulation and reward anticipation.

Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect.

Background: Childhood maltreatment is the most important preventable cause of psychopathology accounting for about 45% of the population attributable risk for childhood onset psychiatric disorders. A key breakthrough has been the discovery that maltreatment alters trajectories of brain development.

Methods: This review aims to synthesize neuroimaging findings in children who experienced caregiver neglect as well as from studies in children, adolescents and adults who experienced physical, sexual and emotional abuse.

Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes.

Objective: Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (major depression, substance abuse, anxiety disorders, and posttraumatic stress disorder) a substantial subset of individuals have a history of maltreatment and a substantial subset do not. The authors examined the evidence to assess whether those with a history of maltreatment represent a clinically and biologically distinct subtype.

Psychiatric treatment of the VIP: some paradoxical risks.

One might expect that VIPs-individuals with wealth, fame, or power-would typically receive excellent care when treated for psychiatric disorders. Often, this is the case, but paradoxically, VIP status may compromise the quality of psychiatric treatment. In this article, we present four case examples, representing disguised amalgamations of actual cases from our experience, demonstrating how VIP patients may sometimes receive suboptimal psychiatric care.

Hurtful words: association of exposure to peer verbal abuse with elevated psychiatric symptom scores and corpus callosum abnormalities.

Objective: Previous studies have shown that exposure to parental verbal abuse in childhood is associated with higher rates of adult psychopathology and alterations in brain structure. In this study the authors sought to examine the symptomatic and neuroanatomic effects, in young adulthood, of exposure to peer verbal abuse during childhood.

Method: A total of 848 young adults (ages 18-25 years) with no history of exposure to domestic violence, sexual abuse, or parental physical abuse rated their childhood exposure to parental and peer verbal abuse and completed a self-report packet that included the Kellner Symptom Questionnaire, the Limbic Symptom Checklist-33, and the Dissociative Experiences Scale.

Length of time between onset of childhood sexual abuse and emergence of depression in a young adult sample: a retrospective clinical report.

Objective: Depression is the most common adult outcome of exposure to childhood sexual abuse (CSA). In this study, we retrospectively assessed the length of time from initial abuse exposure to onset of a major depressive episode.

Method: A community-based survey of childhood experiences in 564 young adults aged 18 to 22 years, conducted between 1997 and 2001, identified 29 right-handed female subjects with CSA but no other exposure to trauma.

Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3).

To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m.

Sticks, stones, and hurtful words: relative effects of various forms of childhood maltreatment.

Objective: Childhood maltreatment is an important psychiatric risk factor. Research has focused primarily on the effects of physical abuse, sexual abuse, or witnessing domestic violence. Parental verbal aggression has received little attention as a specific form of abuse.

Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression?

In summary, our review of the literature suggests that diabetes, especially type 1 diabetes, may place patients at risk for a depressive disorder through a biological mechanism linking the metabolic changes of diabetes to changes in brain structure and function. Further studies are warranted examining these relationships in order to better understand the impact of diabetes on brain functioning and structure as well as one potential manifestation of such changes--affective disorder. Moreover, such studies could play a useful role in better understanding mechanisms that commonly underlie the development of depression in individuals without diabetes but with other medical problems or conditions.

Glycemic control and major depression in patients with type 1 and type 2 diabetes mellitus.

The current study evaluated the association of glycemic control and major depression in 33 type 1 and 39 type 2 diabetes mellitus patients. Type 1 patients with a lifetime history of major depression showed significantly worse glycemic control than patients without a history of psychiatric illness (t = 2.09; df = 31, p < 0.

Hypothalamic-pituitary-adrenal axis effects on plasma homovanillic acid in man.

Background: Effects of the hypothalamic-pituitary-adrenal (HPA) axis on central dopaminergic systems have been proposed to underlie the development of psychotic symptoms in depression. This study examined HPA axis hormone effects on plasma levels of homovanillic acid (HVA), the dopamine metabolite, in healthy volunteers, using a placebo-controlled, double-blind, random-assignment, crossover design. On the basis of preliminary studies, we hypothesized that HPA axis hormones would produce delayed effects on plasma HVA levels measured in the afternoon.

McLean Hospital depression research facility: early-onset phobic disorders and adult-onset major depression.

Background: This study explores the temporal relationship between anxiety and major depressive disorders in a cohort of patients with current major depression.

Method: Current prevalence and lifetime history of specific anxiety disorders were assessed using the Structured Clinical Interview for DSM-III-R Diagnosis (SCID-P) in 85 patients with DSM-III-R major depression. Consensus DSM-III-R diagnoses were assigned by at least two psychiatrists or psychologists.

Signal transduction by platelet adenylate cyclase: alterations in depressed patients may reflect impairment in the coordinated integration of cellular signals (coincidence detection).

Background: Adenylate cyclase (AC) responds to distinct but coincident signals from the agonist-stimulated G-protein Gs and the inhibitory G-protein Gi by generating a greater output signal-to-noise ratio--i.e., agonist-stimulated to basal ratio (fold-stimulation)--through coincidence detection than that generated by a single input (Gs) alone.

Revisiting the factor structure for positive and negative symptoms: evidence from a large heterogeneous group of psychiatric patients.

Objective: The factor structures of individual positive and negative symptoms as well as global ratings were examined in a diagnostically heterogeneous group of subjects.

Method: Subjects were identified through a clinical and family study of patients with major psychoses at a VA medical center and evaluated with the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. For the examination of global-level factor structures (N = 630), both principal-component analysis and factor analysis with orthogonal rotation were used.

The effects of psychiatric disorders and symptoms on quality of life in patients with type I and type II diabetes mellitus.

The purpose of this study was to evaluate the influence of psychiatric symptoms and illness status on the health-related quality of life (HRQOL) of out-patients with Type I and Type II diabetes mellitus. Using a two-stage design, all patients were assessed by two measures of quality of life (Diabetes Quality of Life Measure; Medical Outcome Study Health Survey) and a psychiatric symptoms checklist (SCL-90R). Patients scoring 63 or greater on the global severity index of the SCL-90R and 30% below this cutoff were then evaluated using the Structured Clinical Interview for the DSM-III-R (SCID).

Diurnal variation of plasma cortisol and homovanillic acid in healthy subjects.

We investigated the relationship between plasma levels of cortisol, the dopamine metabolite homovanillic acid (HVA) and norepinephrine in healthy human subjects. Plasma cortisol and HVA levels were measured at 0800h, and in an integrated sampling procedure involving samples every 15 min between 1300 and 1600h. Plasma norepinephrine was measured at 0800 and 1300h.