d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia

The N-methyl-d-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by d-amino acid oxidase. Both d-serine and its metabolizing enzymes are implicated in N-methyl-d-aspartate receptor hypofunction thought to occur in schizophrenia. We studied d-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. d-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, d-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or d-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and d-amino acid oxidase are expressed in human brain and provide some support for aberrant d-serine metabolism in schizophrenia. However, they raise further questions as to the roles of d-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting gross morphometric hippocampal plasticity occurs faster than previously thought

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The role of the 5-HT2C receptor in emotional processing in healthy adults

Serotonin (5-HT) has long been implicated in the pathophysiology of depression and anxiety, and the therapeutic effect of treatments. Several drugs useful in treatment produce either acute or neuroadaptive changes in 5-HT2C receptor activity, and there has been growing interest in how alterations in the 5-HT2C receptor might be important in mediating antidepressant and anxiolytic activity. The neuropsychological hypothesis of drug action implies that the clinical effects of medications active in anxiety and depression are best understood through the effects of these agents on the processing of emotional information. Thus far, however, there has been no systematic attempt to identify the role of the 5-HT2C receptor in drug-induced changes in emotional processing in humans. The current research therefore investigated the effects of drug treatments with 5-HT2C blocking properties on neural and behavioural responses to emotional information in healthy volunteers. An fMRI study demonstrated that a single dose of mirtazapine, an antidepressant with action at the 5-HT2C receptor, reduces activation in regions important in emotional processing, such as the amygdala and the fusiform gyrus, to threat-relevant stimuli. A series of behavioural studies utilized drugs acting, at least in part, as 5-HT2C antagonists and agonists to show that these drugs are able to alter emotional processing, particularly emotional memory. A seven-day administration of mirtazapine was shown to increase the recall of positive versus negative personality characteristics. A single dose of agomelatine, also an antidepressant with putative action at the 5-HT2C receptor, did not increase slow wave sleep, suggesting, the drug had no effect of 5-HT2C blockade in the brain. In Chapter 4, agomelatine and mCPP, a 5-HT2C agonist, also shown to had no significant effect on emotional processing measures, but there was a statistical trend for agomelatine to increase memory for positive stimuli, and for mCPP to increase memory for negative stimuli. These findings suggest that antidepressants may work by altering the bias in emotional processing. Overall, the results of this exploration of the role of the 5-HT2C receptor in emotional processing have contributed to the understanding of antidepressant treatment, and raise new possibilities for the continuation of study in this field

The role of the 5-HT2C receptor in emotional processing in healthy adults

Serotonin (5-HT) has long been implicated in the pathophysiology of depression and anxiety, and the therapeutic effect of treatments. Several drugs useful in treatment produce either acute or neuroadaptive changes in 5-HT2C receptor activity, and there has been growing interest in how alterations in the 5-HT2C receptor might be important in mediating antidepressant and anxiolytic activity. The neuropsychological hypothesis of drug action implies that the clinical effects of medications active in anxiety and depression are best understood through the effects of these agents on the processing of emotional information. Thus far, however, there has been no systematic attempt to identify the role of the 5-HT2C receptor in drug-induced changes in emotional processing in humans. The current research therefore investigated the effects of drug treatments with 5-HT2C blocking properties on neural and behavioural responses to emotional information in healthy volunteers. An fMRI study demonstrated that a single dose of mirtazapine, an antidepressant with action at the 5-HT2C receptor, reduces activation in regions important in emotional processing, such as the amygdala and the fusiform gyrus, to threat-relevant stimuli. A series of behavioural studies utilized drugs acting, at least in part, as 5-HT2C antagonists and agonists to show that these drugs are able to alter emotional processing, particularly emotional memory. A seven-day administration of mirtazapine was shown to increase the recall of positive versus negative personality characteristics. A single dose of agomelatine, also an antidepressant with putative action at the 5-HT2C receptor, did not increase slow wave sleep, suggesting, the drug had no effect of 5-HT2C blockade in the brain. In Chapter 4, agomelatine and mCPP, a 5-HT2C agonist, also shown to had no significant effect on emotional processing measures, but there was a statistical trend for agomelatine to increase memory for positive stimuli, and for mCPP to increase memory for negative stimuli. These findings suggest that antidepressants may work by altering the bias in emotional processing. Overall, the results of this exploration of the role of the 5-HT2C receptor in emotional processing have contributed to the understanding of antidepressant treatment, and raise new possibilities for the continuation of study in this field.EThOS - Electronic Theses Online ServiceGBUnited Kingdo