A platform to induce and mature biomolecular condensates using chemicals and light.

Biomolecular condensates are membraneless compartments that impart spatial and temporal organization to cells. Condensates can undergo maturation, transitioning from dynamic liquid-like states into solid-like states associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Despite their important roles, many aspects of condensate biology remain incompletely understood, requiring tools for acutely manipulating condensate-relevant processes within cells. Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease.

Prevalence of impaired kidney function in patients with long-term lithium treatment: A systematic review and meta-analysis.

OBJECTIVES: Although lithium renal effects have been extensively investigated, prevalence rates of chronic kidney disease (CKD) in lithium-treated patients vary. Our aim was to provide prevalence estimates and related moderators. METHODS: We performed a systematic review in PubMed/Embase until November 01, 2021, conducting a random effects meta-analysis of studies evaluating CKD prevalence rates in lithium-treated patients calculating overall prevalence ±95% confidence intervals (CIs). Meta-regression analyses included sex, age, body mass index, smoking, hypertension, diabetes, cardiovascular disease, lithium-treatment dose, duration, and blood levels. Subgroup analyses included sample size, diagnoses, and study design. Pooled odds ratios (OR) were estimated for studies including patients receiving nonlithium treatment. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: Five, nine, and six trials were rated as high, fair, and low quality, respectively. In 20 studies (n = 25,907 patients), we estimated an overall prevalence of 25.5% (95% CI = 19.8-32.2) of impaired kidney function; despite lack of differences (p = 0.18), prevalence rates were higher in elderly samples than mixed samples of elderly and nonelderly (35.6%, 95% CI = 21.4-52.9, k = 2, n = 3,161 vs. 25.1%, 95% CI = 19.1-31.3, k = 18, n = 22,746). Prevalence rates were associated with longer lithium treatment duration (p = 0.04). Cross-sectional studies provided lower rates than retrospective studies (14.5%, 95% CI = 13.5-15.5, k = 6, n = 4,758 vs. 29.5%, 95% CI = 22.1-38.0, k = 12, n = 17,988, p < 0.001). Compared with 722,529 patients receiving nonlithium treatment, the OR of impaired kidney function in 14,187 lithium-treated patients was 2.09 (95% CI = 1.24-3.51, k = 8, p = 0.005). CONCLUSIONS: One-fourth of patients receiving long-term lithium may develop impaired kidney function, although research suffers from substantial heterogeneity between studies. This risk may be twofold higher compared with nonlithium treatment and may increase for a longer lithium treatment duration.

Exploring Care Attributes of Nephrologists Ranking Favorably on Measures of Value.

BACKGROUND: Despite growth in value-based payment, attributes of nephrology care associated with payer-defined value remains unexplored. METHODS: Using national health insurance claims data from private preferred provider organization plans, we ranked nephrology practices using total cost of care and a composite of common quality metrics. Blinded to practice rankings, we conducted site visits at four highly ranked and three average ranked practices to identify care attributes more frequently present in highly ranked practices. A panel of nephrologists used a modified Delphi method to score each distinguishing attribute on its potential to affect quality and cost of care and ease of transfer to other nephrology practices. RESULTS: Compared with average-value peers, high-value practices were located in areas with a relatively higher proportion of black and Hispanic patients and a lower proportion of patients aged >65 years. Mean risk-adjusted per capita monthly total spending was 24% lower for high-value practices. Twelve attributes comprising five general themes were observed more frequently in high-value nephrology practices: preventing near-term costly health crises, supporting patient self-care, maximizing effectiveness of office visits, selecting cost-effective diagnostic and treatment options, and developing infrastructure to support high-value care. The Delphi panel rated four attributes highly on effect and transferability: rapidly adjustable office visit frequency for unstable patients, close monitoring and management to preserve kidney function, early planning for vascular access, and education to support self-management at every contact. CONCLUSIONS: Findings from this small-scale exploratory study may serve as a starting point for nephrologists seeking to improve on payer-specified value measures.

Systems Delivery Innovation for Alzheimer Disease.

OBJECTIVE: The authors describe a comprehensive care model for Alzheimer disease (AD) that improves value within 1-3 years after implementation by leveraging targeted outpatient chronic care management, cognitively protective acute care, and timely caregiver support. METHODS: Using current best evidence, expert opinion, and macroeconomic modeling, the authors designed a comprehensive care model for AD that improves the quality of care while reducing total per capita healthcare spending by more than 15%. Cost savings were measured as reduced spending by payers. Cost estimates were derived from medical literature and national databases, including both public and private U.S. payers. All estimates reflect the value in 2015 dollars using a consumer price index inflation calculator. Outcome estimates were determined at year 2, accounting for implementation and steady-state intervention costs. RESULTS: After accounting for implementation and recurring operating costs of approximately $9.5 billion, estimated net cost savings of between $13 and $41 billion can be accomplished concurrently with improvements in quality and experience of coordinated chronic care ($0.01-$6.8 billion), cognitively protective acute care ($8.7-$26.6 billion), timely caregiver support ($4.3-$7.5 billion), and caregiver efficiency ($4.1-$7.2 billion). CONCLUSION: A high-value care model for AD may improve the experience of patients with AD while significantly lowering costs.

Interpretation of PROMIS Depression and Anxiety Measures Compared with DSM-5 Diagnostic Criteria in Musculoskeletal Patients.

There is growing awareness among orthopaedic clinicians that mental health directly impacts clinical musculoskeletal outcomes. The Patient-Reported Outcomes Measurement Information System (PROMIS) is increasingly used for mental health screening in this context, but proper interpretation of patient scores remains unclear. The purpose of the present study was to compare musculoskeletal patients' PROMIS Depression and Anxiety scores with a board-certified clinical psychologist's assessment of their depression and/or anxiety diagnoses, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Methods: In this cross-sectional analysis, existing medical records were reviewed for 50 patients who presented to an interdisciplinary program within a tertiary care orthopaedic department for the treatment of ≥1 musculoskeletal condition. All patients completed PROMIS Depression and Anxiety measures and were evaluated by a board-certified clinical psychologist. Receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic accuracy of PROMIS Depression and Anxiety scores as compared with the psychologist's diagnosis of a DSM-5 depressive or anxiety disorder. Results: Twenty-eight patients (56%) were diagnosed by the psychologist with a DSM-5 depressive disorder, and 15 (30%) were diagnosed with a DSM-5 anxiety disorder. The ROC analysis for PROMIS Depression had an area under the curve (AUC) of 0.82. The optimal score cutoff to predict a diagnosis of a DSM-5 depressive disorder was ≥53 (sensitivity, 79% [95% CI, 63% to 94%]; specificity, 86% [72% to 100%]; positive predictive value [PPV], 88% [75% to 100%]; negative predictive value [NPV], 76% [59% to 93%]). The ROC analysis for PROMIS Anxiety had an AUC of 0.67. The optimal score cutoff to predict a diagnosis of a DSM-5 anxiety disorder was ≥59 (sensitivity, 60% [95% CI, 35% to 85%]; specificity, 74% [60% to 89%]; PPV, 50% [27% to 73%]; and NPV, 81% [68% to 95%]). Conclusions: Modestly elevated PROMIS Depression scores were suggestive of the presence of a DSM-5 depressive disorder, whereas elevations in PROMIS Anxiety scores seemed to have less association with DSM-5 anxiety disorders. Nevertheless, neither PROMIS measure demonstrated adequate discriminant ability to definitively identify patients who met DSM-5 criteria. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Influence of Race, Sex, and Social Disadvantage on Self-reported Health in Patients Presenting With Chronic Musculoskeletal Pain.

OBJECTIVE: The aim of the study was to better address sociodemographic-related health disparities. This study examined which sociodemographic variables most strongly correlate with self-reported health in patients with chronic musculoskeletal pain. DESIGN: This single-center, cross-sectional study examined adult patients, followed by a physiatrist for chronic (≥4 yrs) musculoskeletal pain. Sociodemographic variables considered were race, sex, and disparate social disadvantage (measured as residential address in the worst vs. best Area Deprivation Index national quartile). The primary comparison was the adjusted effect size of each variable on physical and behavioral health (measured by Patient-Reported Outcomes Measurement Information System [PROMIS]). RESULTS: In 1193 patients (age = 56.3 ± 13.0 yrs), disparate social disadvantage was associated with worse health in all domains assessed (PROMIS Physical Function Β = -2.4 points [95% confidence interval = -3.8 to -1.0], Pain Interference = 3.3 [2.0 to 4.6], Anxiety = 4.0 [1.8 to 6.2], and Depression = 3.7 [1.7 to 5.6]). Black race was associated with greater anxiety than white race (3.2 [1.1 to 5.3]), and female sex was associated with worse physical function than male sex (-2.5 [-3.5 to -1.5]). CONCLUSIONS: Compared with race and sex, social disadvantage is more consistently associated with worse physical and behavioral health in patients with chronic musculoskeletal pain. Investment to ameliorate disadvantage in geographically defined communities may improve health in sociodemographically at-risk populations.

Opioid use and social disadvantage in patients with chronic musculoskeletal pain.

BACKGROUND: Historically, marginalized patients were prescribed less opioid medication than affluent, white patients. However, because of persistent differential access to nonopioid pain treatments, this direction of disparity in opioid prescribing may have reversed. OBJECTIVE: To compare social disadvantage and health in patients with chronic pain who were managed with versus without chronic opioid therapy. It was hypothesized that patients routinely prescribed opioids would be more likely to live in socially disadvantaged communities and report worse health. DESIGN: Cross-sectional analysis of a retrospective cohort defined from medical records from 2000 to 2019. SETTING: Single tertiary safety net medical center. PATIENTS: Adult patients with chronic musculoskeletal pain who were managed longitudinally by a physiatric group practice from at least 2011 to 2015 (n = 1173), subgrouped by chronic (≥4 years) adherent opioid usage (n = 356) versus no chronic opioid usage (n = 817). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was the unadjusted between-group difference in social disadvantage, defined by living in the worst national quartile of the Area Deprivation Index (ADI). An adjusted effect size was also calculated using logistic regression, with age, sex, race, and Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Physical Function scores as covariates. Secondary outcomes included adjusted differences in health by chronic opioid use (measured by PROMIS). RESULTS: Patients managed with chronic opioid therapy were more likely to live in a zip code within the most socially disadvantaged national quartile (34.9%; 95% confidence interval [CI] 29.9-39.9%; vs. 24.9%; 95% CI 21.9-28.0%; P < .001), and social disadvantage was independently associated with chronic opioid use (odds ratio [OR] 1.01 per ADI percentile [1.01-1.02]). Opioid use was also associated with meaningfully worse PROMIS Depression (3.8 points [2.4-5.1]), Anxiety (3.0 [1.4-4.5]), and Pain Interference (2.6 [1.7-3.5]) scores. CONCLUSIONS: Patients prescribed chronic opioid treatment were more likely to live in socially disadvantaged neighborhoods, and chronic opioid use was independently associated with worse behavioral health. Improving access to multidisciplinary, nonopioid treatments for chronic pain may be key to successfully overcoming the opioid crisis.

Rate of continued conservative management versus progression to surgery at minimum 1-year follow-up in patients with pre-arthritic hip pain.

BACKGROUND: Extensive literature has described surgical outcomes for pre-arthritic hip pain, but the proportion of patients who progress to surgery remains unknown. OBJECTIVE: To determine the proportion of patients who present to a tertiary referral center for pre-arthritic hip pain and progress to surgery at minimum 1-year follow-up. DESIGN: Retrospective cohort study. SETTING: Single tertiary care academic medical center. PATIENTS: Patients ages 13 to 40 years who presented for initial evaluation to a conservative or surgical orthopedic specialist and were diagnosed with pre-arthritic hip pain (n = 713 patients, 830 hips). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was the rate of progression to surgery at minimum 1-year follow-up for the entire cohort. Predictors of progression to surgery were determined for the entire cohort and for radiographically defined subgroups using multiple logistic regression. Candidate predictors included baseline demographic, radiographic, clinical diagnosis, and patient-reported outcome measures. RESULTS: In a cohort with a mean age of 25.4 (SD 8.1) years, 72.7% female, and mean follow-up of 2.6 (range 1.0-4.8) years, 429 of 830 hips (51.7%, 95% confidence interval [CI] 48.2% to 55.1%) progressed to surgery. Predictors of surgical progression in the entire cohort included younger age (OR 0.95/year, 95% CI 0.93 to 0.98), pain duration longer than 6 months (ORs 1.87-2.03, p ≤ .027), worse physical function (OR 0.96/Patient-Reported Outcomes Measurement Information System [PROMIS] point, 0.92 to 0.99), and a clinical diagnosis of femoroacetabular impingement (FAI) (OR 3.47, 2.05 to 5.89), acetabular dysplasia (OR 2.75, 1.73 to 4.35), and/or labral tear (OR 10.71, 6.98 to 16.47). Radiographic dysplasia (lateral center edge angle <20 degrees) increased the likelihood of surgery in all subgroups (ORs 2.05-8.47, p ≤ .008). Increasing maximum α angle increased the likelihood of surgery in patients with severe cam FAI (α > 63 degrees) (OR 1.03/degree, 1.00 to 1.06). CONCLUSION: Almost half of patients with pre-arthritic hip pain did not progress to surgery at a minimum 1-year follow-up. A trial of conservative management is likely worthwhile in most patients.

A laboratory and simulation platform to integrate individual life history traits and population dynamics.

Understanding populations is important because they are a fundamental level of biological organization. Individual traits such as aging and lifespan interact in complex ways to determine birth and death and thereby influence population dynamics. However, we lack a deep understanding of the relationships between individual traits and population dynamics. To address this challenge, we established a laboratory population using the model organism C. elegans and an individual-based computational simulation informed by measurements of real worms. The simulation realistically models individual worms and the behavior of the laboratory population. To elucidate the role of aging in population dynamics, we analyzed old age as a cause of death and showed, using computer simulations, that it was influenced by maximum lifespan, rate of adult culling, and progeny number/food stability. Notably, populations displayed a tipping point for aging as the primary cause of adult death. Our work establishes a conceptual framework that could be used for better understanding why certain animals die of old age in the wild.

Patient-Reported Experiences with Dialysis Care and Provider Visit Frequency.

BACKGROUND AND OBJECTIVES: New payment models resulting from the Advancing American Kidney Health initiative may create incentives for nephrologists to focus less on face-to-face in-center hemodialysis visits. This study aimed to understand whether more frequent nephrology practitioner dialysis visits improved patient experience and could help inform future policy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study of patients receiving dialysis from April 1, 2015 through January 31, 2016, we linked patient records from a national kidney failure registry to patient experience data from the In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems survey. We used a multivariable mixed effects linear regression model to examine the association between nephrology practitioner visit frequency and patient-reported experiences with nephrologist care. RESULTS: Among 5125 US dialysis facilities, 2981 (58%) had ≥30 In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems surveys completed between April 2015 and January 2016, and 243,324 patients receiving care within these facilities had Medicare Parts A/B coverage. Face-to-face practitioner visits per month were 71% with four or more visits, 17% with two to three visits, 4% with one visit, and 8% with no visits. Each 10% absolute greater proportion of patients seen by their nephrology practitioner(s) four or more times per month was associated with a modestly but statistically significant lower score of patient experience with nephrologist care by -0.3 points (95% confidence interval, -0.5 to -0.1) and no effect on experience with other domains of dialysis care. CONCLUSIONS: In an analysis of patient experiences at the dialysis facility level, frequent nephrology practitioner visits to facilities where patients undergo outpatient hemodialysis were not associated with better patient experiences.

Revealing Novel IDEAS: A Fiduciary Framework for Team-Based Prescribing.

The importance of safe, effective, and cost-effective prescribing habits can hardly be overstated in the current pay-for-value environment. The prescribing process taught in most medical curricula focuses primarily on accurate medical indications. While this may be of utmost importance from the clinician's perspective, it falls short of addressing the other key elements of highly effective prescribing. These other elements are often paramount in the minds of patients. A patient-centric framework that associates and incorporates the necessary components of optimal prescribing is overdue. Building this framework into medical curricula will foster increased teamwork among providers and enhance shared decision making between patients and clinicians. In addition to establishing accurate medical indications, prescribing teams need to assure every prescribed medication is desired, effective, affordable, and safe for patients who receive them. Prescription writing is an honorable prerogative, and doing so safely, effectively, and cost-effectively requires both teamwork and technology. Highly effective prescribing teams can implement the IDEAS (Indicated, Desired, Effective, Affordable, Safe) framework through appropriate and deliberate delegation. By empowering members of the care team to support and educate patients, this framework will allow physicians to focus on ensuring appropriate indications and real-world effectiveness. This novel IDEAS framework serves as an important mental model for medical trainees and reinforces sound prescribing habits among seasoned clinicians. High-touch and high-tech partnerships have the potential to maximize the triple aim (i.e., improving the patient's experience of care, improving the health of populations, and reducing the per capita cost of health care). In an era when costs overwhelm quality, providing a fiduciary framework to instill responsibility for optimal prescribing, especially among young physician-leaders, is invaluable.

Patient-Reported Experiences of Dialysis Care Within a National Pay-for-Performance System.

Importance: Medicare's End-Stage Renal Disease Quality Incentive Program incorporates measures of perceived value into reimbursement calculations. In 2016, patient experience became a clinical measure in the Quality Incentive Program scoring system. Dialysis facility performance in patient experience measures has not been studied at the national level to date. Objective: To examine associations among dialysis facility performance with patient experience measures and patient, facility, and geographic characteristics. Design: In this cross-sectional analysis, patients from a national end-stage renal disease registry receiving in-center hemodialysis in the United States on December 31, 2014, were linked with dialysis facility scores on the In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH-CAHPS) survey. Of 4977 US dialysis facilities, 2939 (59.1%) reported ICH-CAHPS scores from April 8, 2015, through January 11, 2016. Multivariable linear regression models with geographic random effects were used to examine associations of facility ICH-CAHPS scores with patient, dialysis facility, and geographic characteristics and to identify the amount of total between-facility variation in patient experience scores explained by these categories. Data were analyzed from September 15, 2017, through June 1, 2018. Exposures: Dialysis facility, geographic characteristic, and 10% change in patient characteristics. Main Outcomes and Measures: Dialysis facility ICH-CAHPS scores and the total between-facility variation explained by different categories of characteristics. Results: Of the 2939 facilities included in the analysis, adjusted mean ICH-CAHPS scores were 2.6 percentage points (95% CI, 1.5-3.7) lower in for-profit facilities, 1.6 percentage points (95% CI, 0.9-2.2) lower in facilities owned by large dialysis organizations, and 2.3 percentage points (95% CI, 0.5-4.2) lower in free-standing facilities compared with their counterparts. More nurses per patient was associated with 0.2 percentage points (95% CI, 0.03-0.3) higher scores; a privately insured patient population was associated with 1.2 percentage points (95% CI, 0.2-2.2) higher scores. Facilities with higher proportions of black patients had 0.95 percentage points (95% CI, 0.78-1.12) lower scores; more Native American patients, 1.00 percentage point (95% CI, 0.39-1.60) lower facility scores. Geographic location and dialysis facility characteristics explained larger proportions of the overall between-facility variation in ICH-CAHPS scores than did patient characteristics. Conclusions and Relevance: This study suggests that for-profit operation, free-standing status, and large dialysis organization designation were associated with less favorable patient-reported experiences of care. Patient experience scores varied geographically, and black and Native American populations reported less favorable experiences. The study findings suggest that perceived quality of care delivered in these settings are of concern, and that there may be opportunities for improved implementation of patient experience surveys as is highlighted.

A multicenter phase IIb study of a novel combination of intramuscular androgen (testosterone decanoate) and oral progestogen (etonogestrel) for male hormonal contraception.

The effect of a novel combination of oral etonogestrel (ENG) and im testosterone decanoate (TD) on suppression of gonadotropins and spermatogenesis as a potential lead for male contraception was investigated. Healthy male volunteers were randomized into two groups receiving 300 microg ENG daily and 400 mg TD every 4 (n = 55) or 6 (n = 57) wk for 48 wk. At wk 48, all men except one in the 6-wk group suppressed sperm concentration to less than 1 million/ml. Faster suppression occurred in the 4-wk group. Gonadotropins were suppressed in both groups and most consistently in the 4-wk group. During treatment, trough testosterone levels increased into the normal range in the 4-wk group but remained just below normal in the 6-wk group. All peak levels were within the normal range. After treatment cessation, recovery of sperm counts and gonadotropins to normal levels occurred in both groups. Minor effects on weight and cholesterol were noted. Fourteen subjects withdrew because of an adverse event with those possibly related to the study medication reported more frequently in the 6-wk group (nine vs. one). In conclusion, the combination of 300 microg ENG with 400 mg TD every 4 wk was superior in terms of efficacy, hormone profiles, and safety. This represents a promising approach to male hormonal contraception.

Advances in male contraception.

Advances in contraception have been almost exclusively female-directed despite the widespread use of male methods worldwide and increasing calls for the burden of contraception to be more evenly shared. Of the several potential approaches to novel male methods, the hormonal approach is the nearest to fruition. The use of testosterone as a reversible contraceptive agent in men has been demonstrated in studies undertaken by the WHO over the last decade. However, an agent that results in universal azoospermia without significant side effects remains elusive. Consequently, combination approaches with progestogens, anti-androgens, 5 alpha-reductase inhibitors and gonadotrophin-releasing hormone (GnRH) antagonists have been evaluated with the aim of improving contraceptive efficacy. Different methods of androgen delivery are also being developed in order to minimise extra-testicular effects and improve acceptability. This review will focus on efforts to develop a safe, acceptable, efficacious hormonal contraceptive for men.

Binaural beat induced theta EEG activity and hypnotic susceptibility: contradictory results and technical considerations.

The present study offered a constructive replication of an earlier study which demonstrated significant increases in theta EEG activity following theta binaural beat (BB) entrainment training and significant increases in hypnotic susceptibility. This study improved upon the earlier small-sample, multiple-baseline investigation by employing a larger sample, by utilizing a double-blind, repeated-measures group experimental design, by investigating only low and moderate susceptible participants, and by providing 4 hours of binaural beat training. With these design improvements, results were not supportive of the specific efficacy of the theta binaural beat training employed in this study in either increasing frontal theta EEG activity or in increasing hypnotic susceptibility. Statistical power analyses indicated the theta binaural beat training to be a very low power phenomenon on theta EEG activity. Furthermore, we found no significant relationship between frontal theta power and hypnotizability, although the more hypnotizable participants showed significantly greater increases in hypnotizability than the less hypnotizables. Results are discussed within the context of participant selection and classification factors, technical considerations in the presentation of TBB training, and theta blocking.

Electrophysiological alterations during hypnosis for ego-enhancement: a preliminary investigation.

EEG activity at the midfrontal (Fz) region was recorded during pre- and postbaselines, live hypnotic induction, arm levitation and progressive relaxation (PNR) deepening, and therapeutic ego-enhancing suggestions among 60 college student volunteers, previously screened with the Stanford Hypnotic Susceptibility Scale, Form C. Comparisons across conditions for delta, theta, alpha, and beta activity were made between low, moderate, high, and very high hypnotizable groups. Results indicated (a) significant increases in theta EEGs across the hypnosis process with a peak at PNR and a drop in theta thereafter to termination, with highs showing significantly more dramatic effects than moderates; (b) a similar inverted U-shaped pattern for beta EEGs across hypnosis conditions, with very highs significantly higher in beta power than moderates and lows, and with highs significantly higher than moderates; (c) general profile differences between the highs for theta and the highs and very highs for beta in comparison to the moderates and lows, with peak theta and beta power occurring during ego-enhancing suggestions for more highly hypnotizable participants; (d) a drop in alpha EEGs across the trance process with a return to baseline after hypnosis, with moderates showing significantly lower alpha power; and (e) an increase in delta power across conditions to PNR and then a decrease to post-hypnosis baseline, with moderates significantly lower than highs.

Regulation of CPSase, ACTase, and OCTase genes in Medicago truncatula: Implications for carbamoylphosphate synthesis and allocation to pyrimidine and arginine de novo biosynthesis.

In most prokaryotes and many eukaryotes, synthesis of carbamoylphosphate (CP) by carbamoylphosphate synthetase (CPSase; E.C. 6.3.5.5) and its allocation to either pyrimidine or arginine biosynthesis are highly controlled processes. Regulation at the transcriptional level occurs at either CPSase genes or the downstream genes encoding aspartate carbamoyltransferase (E.C. 2.1.3.2) or ornithine carbamoyltransferase (E.C. 2.1.3.3). Given the importance of pyrimidine and arginine biosynthesis, our lack of basic knowledge regarding genetic regulation of these processes in plants is a striking omission. Transcripts encoding two CPSase small subunits (MtCPSs1 and MtCPSs2), a single CPSase large subunit (MtCPSl), ACTase (MtPyrB), and OCTase (MtArgF) were characterized in the model legume Medicago truncatula. Quantitative real-time PCR data provided evidence (i) that the accumulation of all CPSase gene transcripts, as well as the MtPyrB transcript, was dramatically reduced following seedling incubation with uridine; (ii) exogenously supplied arginine down regulated only MtArgF; and (iii) mRNA levels of both CPSase small subunits, MtPyrB, and MtArgF were significantly increased after supplying plants with ornithine alone or in combination with uridine or arginine compared to plants treated with only uridine or arginine, respectively (P< or =0.05). A proposed novel, yet simple regulatory scheme employed by M. truncatula more closely resembles a prokaryotic control strategy than those used by other eukaryotes.