Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.

Influence of marine habitat on microplastic prevalence in forage fish and salmon in the Salish Sea.

Microplastics are increasingly prevalent in marine systems and are a growing concern as a marine pollutant and contaminant with consequences for high trophic level consumers, including humans. Given evidence that links plastics to degraded ecosystem functioning and organismal health, there is increased interest in understanding the prevalence, fate and consequences of marine plastics. Microplastics contain and absorb harmful chemicals which may serve as endocrine disruptors and have negative implications for growth, reproductive health, and longevity. To expand current knowledge on microplastics in coastal marine ecosystems and the potential for biomagnification in marine food webs, we conducted stomach analyses of microplastics in Pacific salmon (Oncorhynchus spp.) and Pacific sand lance (Ammodytes personatus), an important prey for salmon. Prevalence of microplastics was substantial; 77 % of all salmon and 25 % of all sand lance stomachs contained at least one microplastic. Fish were sampled at multiple sites throughout the inland Salish Sea, including beaches and sediment bedforms for Pacific sand lance and open-water pelagic habitat for Pacific salmon. Pacific sand lance sampled at beach sites had more microplastics compared to those sampled in subtidal sediments and there were more plastics in sand lance at a protected beach site as compared to an exposed beach site. Prevalence of plastics in salmon differed according to species and included analyses of pink salmon (Oncorhynchus gorbuscha), Chinook (Oncorhynchus tshawytscha), and Coho salmon (Oncorhynchus kisutch); plastics were predominantly fibers in all species, though there were relatively higher rates of ingestion of films and particles in Chinook. Comparisons between plastic concentrations and stomach fullness indicated a slight negative trend, suggesting that plastics may be retained. Further investigation is needed to develop a more thorough understanding of the prevalence and fate of microplastics in coastal marine systems such as the Salish Sea, their concentration within marine food webs, and the implications for species targeted in fisheries.

Npas4a expression in the teleost forebrain is associated with stress coping style differences in fear learning.

Learning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal's stress coping style (e.g. proactive-reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles.

Controlled experiments to explore the use of a multi-tissue approach to characterizing stress in wild-caught Pacific halibut (Hippoglossus stenolepis).

The integration of multiple tissues in physiological and ecological analyses can enhance methodological approaches, increase applications for data and extend interpretation of results. Previous investigations of the stress response in fish have focused primarily on cortisol levels in a single matrix-blood plasma-which confines interpretations of cortisol levels to a short temporal frame. Epidermal mucus has been proposed as an alternative or complement to plasma that may provide a view to cortisol levels over a different temporal window allowing comparative assessment. Here, we explore the potential for multi-tissue cortisol analysis using both plasma and epidermal mucus in Pacific halibut (Hippoglossus stenolepis). The relative timing at which cortisol increased and decreased in the two matrices as well as cortisol concentrations at estimated peak levels were compared in two trials after (i) inducing cortisol synthesis by adrenocorticotropic hormone (ACTH1-24) administration and (ii) inducing cortisol elimination using cortisol (hydrocortisone, 98%) injection. The ACTH treatment elicited a peak plasma cortisol response approximately 12 hours post-injection, while mucus cortisol concentrations peaked later at approximately 62 hours post-injection. Exogenous cortisol treatments suggested relatively little transfer of cortisol from plasma to mucus, potentially reflecting differential effects of endogenous and exogenous cortisol. Our results suggest the potential utility of mucus as a sampling matrix that provides an extended window for detection of the stress response as compared to plasma. Results also suggest the utility of a multi-tissue approach to cortisol analysis with potential applications to applied fisheries research. Increased understanding of the relative scale of the cortisol response to stress (e.g. capture) will allow researchers and managers to better interpret the physiological condition and survival outcome of fish subjected to regulatory discard.

Contextual fear learning and memory differ between stress coping styles in zebrafish.

Animals frequently overcome stressors and the ability to learn and recall these salient experiences is essential to an individual's survival. As part of an animal's stress coping style, behavioral and physiological responses to stressors are often consistent across contexts and time. However, we are only beginning to understand how cognitive traits can be biased by different coping styles. Here we investigate learning and memory differences in zebrafish (Danio rerio) displaying proactive and reactive stress coping styles. We assessed learning rate and memory duration using an associative fear conditioning paradigm that trained zebrafish to associate a context with exposure to a natural olfactory alarm cue. Our results show that both proactive and reactive zebrafish learn and remember this fearful association. However, we note significant interaction effects between stress coping style and cognition. Zebrafish with the reactive stress coping style acquired the fear memory at a significantly faster rate than proactive fish. While both stress coping styles showed equal memory recall one day post-conditioning, reactive zebrafish showed significantly stronger recall of the conditioned context relative to proactive fish four days post-conditioning. Through understanding how stress coping strategies promote biases in processing salient information, we gain insight into mechanisms that can constrain adaptive behavioral responses.

Phosphate amendments for chemical immobilization of uranium in contaminated soil.

Uranium (U) contamination is a major environmental problem associated with the mining and processing of nuclear materials for both weapons and power production. When possible, in situ soil remediation techniques are preferable for reducing the risk associated with diffuse low-level U contamination. Uranium is known to form sparingly soluble phosphate compounds that persist in the environment. Therefore, batch experiments were performed to evaluate the efficacy of three phosphate amendments, hydroxyapatite (HA), sodium phytate (IP6) and sodium tripolyphosphate (TPP), to immobilize U in contaminated sediments. The amendments were added at equivalent phosphorus (P) concentrations and then equilibrated under a range of test conditions, with changes in soluble U and Ptotal monitored at pre-set time intervals. Only HA was effective at reducing the soluble U soil fraction when compared to the control, with IP6 and TPP increasing the soluble U soil fraction. After equilibration, changes in contaminant partitioning in the amended sediments were evaluated using operational extraction methods. Sequential extraction results for HA generally indicated a transfer of U from labile to more recalcitrant phases, while the results for IP6 and TPP were more ambiguous.

Repeatability and reliability of exploratory behavior in proactive and reactive zebrafish, Danio rerio.

Behavioral responses to novel situations often vary and can belong to a suite of correlated behaviors. Characteristic behaviors of different personality types (e.g. stress coping styles) are generally consistent across contexts and time. Here, we compare the repeatability and reliability of exploratory behaviors between zebrafish strains selectively bred to display contrasting behavioral responses to stressors that represent the proactive-reactive axis. Specifically, we measure exploratory behavior of individual fish in an open field test over five weeks. We quantified the stationary time, average swimming speed and time spent by a fish in the center area. We found a number of strain differences for each behavioral measure. Stationary time was the most repeatable and reliable measure for assessing proactive-reactive behavioral differences. Reactive zebrafish generally showed the highest reliability and repeatability of exploratory behavior compared to proactive zebrafish and a separate wild caught strain. Given the increased interest in the evolutionary consequences and proximate mechanisms of consistent individual differences, it will be important to continue to investigate how different selective pressures may influence expression of stress coping styles and their effects on the consistency of an animal's behavior.

Therapeutic Lifestyle Changes: Impact on Weight, Quality of Life, and Psychiatric Symptoms in Veterans With Mental Illness.

INTRODUCTION: Veterans with mental illness tend to have shorter life spans and suboptimal physical health because of a variety of factors. These factors include poor nutrition, being overweight, and smoking cigarettes. Nonphysical contributors that may affect quality of life are the stigma associated with mental illness, social difficulties, and spiritual crises. Current mental health treatment focuses primarily on the delivery of medication and evidence-based psychotherapies, which may not affect all the above areas of a Veteran's life as they focus primarily on improving psychological symptoms. Clinicians may find greater success using integrative, comprehensive, multifaceted programs to treat these problems spanning the biological, psychological, social, and spiritual domains. These pilot studies test an adjunctive, holistic, behavioral approach to treat mental illness. This pilot work explores the hypotheses that engagement in a greater number of therapeutic lifestyle changes (TLCs) leads to improvement in quality of life, reduction of psychiatric symptoms, and weight loss. MATERIALS AND METHODS: Institutional Review Boards for human subjects at the Veterans Affairs (VA) Greater Los Angeles and Long Beach Healthcare Systems approved pilot study activities at their sites. Pilot Study 1 was a prospective survey study of Veterans with mental illness, who gained weight on an atypical antipsychotic medication regimen, participating in a weight management study. At each session of the 1-year study, researchers asked a convenience sample of 55 Veterans in the treatment arm whether they engaged in each of the eight TLCs: exercise, nutrition/diet, stress management and relaxation, time in nature, relationships, service to others, religious or spiritual involvement, and recreation. Pilot Study 2 applied the TLC behavioral intervention and examined 19 Veterans with mental illness, who attended four classes about TLCs, received individual counseling over 9 weeks, and maintained journals to track TLC practice. Besides weekly journals, researchers also collected prospective data on quality of life, psychiatric symptoms, vitals, and anthropometric measurements. In both studies, investigators tested for main effects of the total number of TLCs practiced and study week using mixed-effects linear models with independent intercepts by participant. RESULTS: In Study 1, engagement in more TLC behaviors was significantly associated with higher ratings of quality of life, as well as greater weight loss for each additional type of TLC practiced. In Study 2, TLC practice increased significantly over 9 weeks, and was significantly associated with improvements in quality of life and diastolic blood pressure. CONCLUSION: Counseling Veterans to practice TLCs provides a holistic adjunct to current treatments for mental illness. TLCs may confer multiple benefits upon Veterans with mental illness, enhancing quality of life and well-being along with weight management efforts. As these were pilot studies, the samples sizes were relatively small and a control group was lacking. Our findings may have broader implications supporting a holistic approach in both primary and mental health care settings. Future research will expand this work to address its weaknesses and examine the cost differential between this holistic approach and traditional mental health treatment.

Let's Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder.

A pilot study suggested that a dance-class program promoted well-being, self-confidence, and stress reduction for veterans with PTSD.

Meal replacements as a weight loss tool in a population with severe mental illness.

Weight gain and worsening metabolic parameters are often side effects of antipsychotic medications used by individuals with severe mental illness. To address this, a randomized, controlled research study of a behavioral weight management program for individuals with severe mental illness was undertaken to assess its efficacy. Patients unable to meet weight loss goals during the first portion of the year-long study were given the option of using meal replacement shakes in an effort to assist with weight loss. Specific requirements for use of meal replacement shakes were specified in the study protocol; only five patients were able to use the shakes in accordance with the protocol and lose weight while improving metabolic parameters. Case studies of two subjects are presented, illustrating the challenges and obstacles they faced, as well as their successes. Taking responsibility for their own weight loss, remaining motivated through the end of the study, and incorporating the meal replacement shakes into a daily routine were factors found in common with these patients. Use of meal replacements shakes with this population may be effective.

Yoga-Based Classes for Veterans With Severe Mental Illness: Development, Dissemination, and Assessment.

Throughout 8 weeks of yoga-based wellness classes, veterans were assessed for perceived benefits, pain, stress, and biological, psychological, social, and spiritual wellness.

Accounting for escape mortality in fisheries: implications for stock productivity and optimal management.

Few studies have considered the management implications of mortality to target fish stocks caused by non-retention in commercial harvest gear (escape mortality). We demonstrate the magnitude of this previously unquantified source of mortality and its implications for the population dynamics of exploited stocks, biological metrics, stock productivity, and optimal management. Non-retention in commercial gillnet fisheries for Pacific salmon (Oncorhynchus spp.) is common and often leads to delayed mortality in spawning populations. This represents losses, not only to fishery harvest, but also in future recruitment to exploited stocks. We estimated incidence of non-retention in Alaskan gillnet fisheries for sockeye salmon (O. nerka) and found disentanglement injuries to be extensive and highly variable between years. Injuries related to non-retention were noted in all spawning populations, and incidence of injury ranged from 6% to 44% of escaped salmon across nine river systems over five years. We also demonstrate that non-retention rates strongly correlate with fishing effort. We applied maximum likelihood and Bayesian approaches to stock-recruitment analyses, discounting estimates of spawning salmon to account for fishery-related mortality in escaped fish. Discounting spawning stock estimates as a function of annual fishing effort improved model fits to historical stock-recruitment data in most modeled systems. This suggests the productivity of exploited stocks has been systematically underestimated. It also suggests that indices of fishing effort may be used to predict escape mortality and correct for losses. Our results illustrate how explicitly accounting for collateral effects of fishery extraction may improve estimates of productivity and better inform management metrics derived from estimates of stock-recruitment analyses.

Injuries from non-retention in gillnet fisheries suppress reproductive maturation in escaped fish.

Exploitation of fisheries resources has unintended consequences, not only in the bycatch and discard of non-target organisms, but also in damage to targeted fish that are injured by gear but not landed (non-retention). Delayed mortality due to non-retention represents lost reproductive potential in exploited stocks, while not contributing to harvest. Our study examined the physiological mechanisms by which delayed mortality occurs and the extent to which injuries related to disentanglement from commercial gear compromise reproductive success in spawning stocks of Pacific salmon (Oncorhynchus spp.). We found evidence for elevated stress in fish injured via non-retention in gillnet fisheries. Plasma cortisol levels correlated with the severity of disentanglement injury and were elevated in fish that developed infections related to disentanglement injuries. We also analyzed sex steroid concentrations in females (estradiol-17ß and 17,20ß-dihydroxy-4-pregnen-3-one) to determine whether non-retention impairs reproductive potential in escaped individuals. We demonstrate evidence for delayed or inhibited maturation in fish with disentanglement injuries. These findings have important implications for effective conservation and management of exploited fish stocks and suggest means to improve spawning success in such stocks if retention in commercial fisheries is improved and incidental mortality reduced.

The aminoglycoside resistance methyltransferases from the ArmA/Rmt family operate late in the 30S ribosomal biogenesis pathway.

Bacterial resistance to 4,6-type aminoglycoside antibiotics, which target the ribosome, has been traced to the ArmA/RmtA family of rRNA methyltransferases. These plasmid-encoded enzymes transfer a methyl group from S-adenosyl-L-methionine to N7 of the buried G1405 in the aminoglycoside binding site of 16S rRNA of the 30S ribosomal subunit. ArmA methylates mature 30S subunits but not 16S rRNA, 50S, or 70S ribosomal subunits or isolated Helix 44 of the 30S subunit. To more fully characterize this family of enzymes, we have investigated the substrate requirements of ArmA and to a lesser extent its ortholog RmtA. We determined the Mg+² dependence of ArmA activity toward the 30S ribosomal subunits and found that the enzyme recognizes both low Mg+² (translationally inactive) and high Mg+² (translationally active) forms of this substrate. We tested the effects of LiCl pretreatment of the 30S subunits, initiation factor 3 (IF3), and gentamicin/kasugamycin resistance methyltransferase (KsgA) on ArmA activity and determined whether in vivo derived pre-30S ribosomal subunits are ArmA methylation substrates. ArmA failed to methylate the 30S subunits generated from LiCl washes above 0.75 M, despite the apparent retention of ribosomal proteins and a fully mature 16S rRNA. From our experiments, we conclude that ArmA is most active toward the 30S ribosomal subunits that are at or very near full maturity, but that it can also recognize more than one form of the 30S subunit.

Selection due to nonretention mortality in gillnet fisheries for salmon.

Fisheries often exert selective pressures through elevated mortality on a nonrandom component of exploited stocks. Selective removal of individuals will alter the composition of a given population, with potential consequences for its size structure, stability and evolution. Gillnets are known to harvest fish according to size. It is not known, however, whether delayed mortality due to disentanglement from gillnets exerts selective pressures that reinforce or counteract harvest selection. We examined gillnet disentanglement in exploited populations of sockeye salmon (Oncorhynchus nerka) in Bristol Bay, Alaska, to characterize the length distribution of fish that disentangle from gillnets and determine whether nonretention mortality reinforces harvest selection and exerts common pressures according to sex and age. We also evaluated discrete spawning populations to determine whether nonretention affects populations with different morphologies in distinct ways. In aggregate, nonretention mortality in fish that disentangle from gillnets counters harvest selection but with different effects by sex and age. At the level of individual spawning populations, nonretention mortality may exert stabilizing, disruptive, or directional selection depending on the size distribution of a given population. Our analyses suggest nonretention mortality exerts significant selective pressures and should be explicitly included in analyses of fishery-induced selection.

Bioaccumulation and transport of contaminants: migrating sockeye salmon as vectors of mercury.

Biological transport by migratory animals is increasingly recognized as important to the long-range dispersal of toxic contaminants. Mercury (Hg) contamination is a widespread environmental concern with serious health implications for humans and wildlife. Due to their unique life history, anadromous salmon may act as important vectors for this contaminant, transferring Hg between marine and freshwater ecosystems. Previous analyses have considered contaminant transport by salmon to be unidirectional. These studies have evaluated Hg import to freshwater by spawning adults, but have not quantitatively assessed export through the migration of juveniles to the ocean. To determine the total Hg burden to freshwater systems by sockeye salmon, we reconstructed the net transport of Hg to the Wood River System in Bristol Bay, Alaska accounting for fluxes in (via adults) and out (via juveniles) of the system. Hg concentrations were higher in juvenile than adult salmon. Hg export from freshwater systems by salmon ranged from 3 to 30% of total import. Proportional export by smolts may be higher for populations under heavy exploitation with strong density dependence in juvenile recruitment. Full consideration of contaminant loading by migratory species requires attention to the relative contaminant flux at all life history stages and the effects of density dependent growth and survival.

Scintillation proximity assay for measurement of RNA methylation.

Methylation of RNA by methyltransferases is a phylogenetically ubiquitous post-transcriptional modification that occurs most extensively in transfer RNA (tRNA) and ribosomal RNA (rRNA). Biochemical characterization of RNA methyltransferase enzymes and their methylated product RNA or RNA-protein complexes is usually done by measuring the incorporation of radiolabeled methyl groups into the product over time. This has traditionally required the separation of radiolabeled product from radiolabeled methyl donor through a filter binding assay. We have adapted and optimized a scintillation proximity assay (SPA) to replace the more costly, wasteful and cumbersome filter binding assay and demonstrate its utility in studies of three distinct methyltransferases, RmtA, KsgA and ErmC'. In vitro, RmtA and KsgA methylate different bases in 16S rRNA in 30S ribosomal particles, while ErmC' most efficiently methylates protein-depleted or protein-free 23S rRNA. This assay does not utilize engineered affinity tags that are often required in SPA, and is capable of detecting either radiolabeled RNA or RNA-protein complex. We show that this method is suitable for quantitating extent of RNA methylation or active RNA methyltransferase, and for testing RNA-methyltransferase inhibitors. This assay can be carried out with techniques routinely used in a typical biochemistry laboratory or could be easily adapted for a high throughput screening format.

Significant postoperative refractive errors in vivo with the Mentor Memorylens intraocular lens.

PURPOSE: To determine the difference between the predicted and postoperative refraction in eyes after implantation of the Mentor MemoryLens intraocular lens (IOL) and compare these results with those of 2 other types of foldable IOLs implanted by the same surgeons. SETTING: Community-based group practice ophthalmology clinic. METHODS: All operated eyes (341) of all patients who had routine phacoemulsification with implantation of a MemoryLens IOL performed by 1 of 2 surgeons were evaluated retrospectively. The predicted refractive error and actual postoperative refractive error were compared in each eye in the MemoryLens group and in 2 smaller control groups with an AcrySof acrylic (Alcon) or SI-40 silicone (Allergan Medical Optics) IOL implanted by the same surgeons using identical technique and IOL calculation parameters. Patients in whom the difference between the predicted and actual postoperative refraction fell significantly outside expected parameters were rechecked with repeat axial length and keratometric readings, and these measurements were used to back-calculate the effective in vivo IOL power. RESULTS: The MemoryLens group had significantly greater variability in postoperative refractive results from those predicted by the Hoffer program than the 2 control groups. The postoperative refractive error in the MemoryLens group differed from +1.50 to -5.50 diopters (D) from that predicted by the IOL calculation formulas. When the outlier groups (ie, greater than +0.50 D or less than -1.00 D from predicted refractive error) were evaluated and compared to the rest of the MemoryLens group and the 2 control groups, no significant difference in axial length, keratometric measurements, operative surgeon, surgical technique, or patient age was found. Repeat axial length and keratometric measurements in the outlier group were not significantly different from those in the same eyes preoperatively. Back-calculation using postoperative axial length and keratometric measurements in the highly myopic outlier group showed that the mean difference between the labeled IOL power and actual in vivo IOL power in the outlier group was -3.08 D (range -1.98 to -7.54 D). The best corrected visual acuity was not affected in patients in the outlier groups despite the refractive variability. CONCLUSION: The variation in postoperative refractive results in the MemoryLens group was significantly greater than in the 2 other foldable IOL groups.