Jumping to attributions during social evaluation.

Social learning is crucial for human relationships and well-being. Self- and other- evaluations are universal experiences, playing key roles in many psychiatric disorders, particularly anxiety and depression. We aimed to deepen our understanding of the computational mechanisms behind social learning, which have been implicated in internalizing conditions like anxiety and depression. We built on prior work based on the Social Evaluation Learning Task (SELT) and introduced a new computational model to better explain rapid initial inferences and progressive refinement during serial social evaluations. The Social Evaluation Learning Task-Revised (SELT-R) was improved by stakeholder input, making it more engaging and suitable for adolescents. A sample of 130 adults from the UK completed the SELT-R and questionnaires assessing symptoms of depression and anxiety. 'Classify-refine' computational models were compared with previously successful Bayesian models. The 'classify-refine' models performed better, providing insight into how people infer the attributes and motives of others. Parameters of the best fitting model from the SELT-R were correlated with Anxiety factor scores, with higher symptoms associated with greater decision noise and higher (less flexible) policy certainty. Our results replicate findings regarding the classify-refine process and set the stage for future investigations into the cognitive mechanisms of self and other evaluations in internalizing disorders.

COVID-19 is associated with early emergence of preeclampsia: results from a large regional collaborative.

Objective: To investigate the relationship between preeclampsia and SARS-CoV-2 infection during pregnancy. Methods: This was a retrospective cohort study of pregnant women between March and October 2020. Pregnant patients admitted to 14 obstetrical centers in Michigan, USA formed the study population. Of the N = 1458 participants, 369 had SARS-CoV-2 infection (cases). Controls were uninfected pregnancies that were delivered in the same obstetric unit within 30 days of the index case. Robust Poisson regression was used to estimate relative risk (RR) of preterm and term preeclampsia and preeclampsia involving placental lesions. The analysis included adjustment for relevant clinical and demographic risk factors.Results: SARS-CoV-2 infection during pregnancy increased the risk of preeclampsia [adjusted aRR = 1.69 (1.26-2.26)], preeclampsia involving placental lesions [aRR = 1.97(1.14-3.4)] and preterm preeclampsia 2.48(1.48-4.17). Although the highest rate of preeclampsia was observed in patients infected with SARS-CoV-2 who were symptomatic (18.4%), there was increased risk even in asymptomatic SARS-CoV-2 infected patients (14.2%) relative to non-infected controls (8.7%) (p < 0.05). This association with symptomatology was also noted with preterm preeclampsia for which the rate doubled from 2.7% in controls to 5.2% in asymptomatic cases and reached 11.8% among symptomatic cases (p < 0.05). The rate of preterm preeclampsia among cases of pregnant people self-identified as Black reached 10.1% and was almost double the rate of the reminder of the group of infected pregnancies (5.3%), although the rate among uninfected was almost the same (2.7%) for both Black and non-Black groups (interaction p = 0.05).Conclusions: Infection with SARS-CoV-2 increases the risk of preeclampsia even in the absence of symptoms, although symptomatic persons are at even higher risk. Racial disparities in the development of preterm preeclampsia after SARS-CoV-2 infection may explain discrepancies in prematurity between different populations.

Maternal SARS-COV-2 infection and prematurity: the Southern Michigan COVID-19 collaborative.

OBJECTIVE: COVID-19 has been reported to increase the risk of prematurity, however, due to the frequent absence of unaffected controls as well as inadequate accounting for confounders in many studies, the question requires further investigation. We sought to determine the impact of COVID-19 disease on preterm birth (PTB) overall, as well as related subcategories such as early prematurity, spontaneous, medically indicated preterm birth, and preterm labor (PTL). We assessed the impact of confounders such as COVID-19 risk factors, a-priori risk factors for PTB, symptomatology, and disease severity on rates of prematurity. METHODS: This was a retrospective cohort study of pregnant women from March 2020 till October 1st, 2020. The study included patients from 14 obstetric centers in Michigan, USA. Cases were defined as women diagnosed with COVID-19 at any point during their pregnancy. Cases were matched with uninfected women who delivered in the same unit, within 30 d of the delivery of the index case. Outcomes of interest were frequencies of prematurity overall and subcategories of preterm birth (early, spontaneous/medically indicated, preterm labor, and premature preterm rupture of membranes) in cases compared to controls. The impact of modifiers of these outcomes was documented with extensive control for potential confounders. A p value <.05 was used to infer significance. RESULTS: The rate of prematurity was 8.9% in controls, 9.4% in asymptomatic cases, 26.5% in symptomatic COVID-19 cases, and 58.8% among cases admitted to the ICU. Gestational age at delivery was noted to decrease with disease severity. Cases were at an increased risk of prematurity overall [adjusted relative risk (aRR) = 1.62 (1.2-2.18)] and of early prematurity (<34 weeks) [aRR = 1.8 (1.02-3.16)] when compared to controls. Medically indicated prematurity related to preeclampsia [aRR = 2.46 (1.47-4.12)] or other indications [aRR = 2.32 (1.12-4.79)], were the primary drivers of overall prematurity risk. Symptomatic cases were at an increased risk of preterm labor [aRR = 1.74 (1.04-2.8)] and spontaneous preterm birth due to premature preterm rupture of membranes [aRR = 2.2(1.05-4.55)] when compared to controls and asymptomatic cases combined. The gestational age at delivery followed a dose-response relation with disease severity, as more severe cases tended to deliver earlier (Wilcoxon p < .05). CONCLUSIONS: COVID-19 is an independent risk factor for preterm birth. The increased preterm birth rate in COVID-19 was primarily driven by medically indicated delivery, with preeclampsia as the principal risk factor. Symptomatic status and disease severity were significant drivers of preterm birth.

Sex ratio and the evolution of aggression in fruit flies.

Aggressive behaviours are among the most striking displayed by animals, and aggression strongly impacts fitness in many species. Aggression varies plastically in response to the social environment, but we lack direct tests of how aggression evolves in response to intra-sexual competition. We investigated how aggression in both sexes evolves in response to the competitive environment, using populations of Drosophila melanogaster that we experimentally evolved under female-biased, equal, and male-biased sex ratios. We found that after evolution in a female-biased environment-with less male competition for mates-males fought less often on food patches, although the total frequency and duration of aggressive behaviour did not change. In females, evolution in a female-biased environment-where female competition for resources is higher-resulted in more frequent aggressive interactions among mated females, along with a greater increase in post-mating aggression. These changes in female aggression could not be attributed solely to evolution either in females or in male stimulation of female aggression, suggesting that coevolved interactions between the sexes determine female post-mating aggression. We found evidence consistent with a positive genetic correlation for aggression between males and females, suggesting a shared genetic basis. This study demonstrates the experimental evolution of a behaviour strongly linked to fitness, and the potential for the social environment to shape the evolution of contest behaviours.

Implementing Clinical Pharmacists in Primary Care: Care Team Satisfaction Survey Results.

BACKGROUND: The rising demand on primary care providers encourages innovative use of care extenders, such as primary care pharmacists. Our academic medical center includes 34 multidisciplinary primary care clinics that provide general pediatric and adolescent medicine, internal medicine, and family medicine services. Primary care pharmacy services (PCPS) have grown since 2016 across 13 clinics serving internal and family medicine services. This study evaluated care team member satisfaction and workflow implications with current PCPS and systematically identified priorities for future expanded services. METHODS: A 15-question survey was developed and administered through an online platform targeting multidisciplinary care team members. Likert and ranked scale responses were averaged by the electronic survey platform to calculate overall composite scores or weighted averages for each question. RESULTS: The survey response rate was 24.7%. There was a high level of agreement among care team members about the satisfaction with currently provided PCPS (range 3-5; mean 4.65 ± 0.66). Care team members disagreed with the perception of increased clinical burden from the PCPS (range 1-5; mean 1.82 ± 1.13). The most beneficial components of current PCPS included hypertension medication management and clinical consult activities (composite scores 3.8 and 3.19, respectively). The highest priority future PCPS identified was diabetes medication management (composite score 4.21). DISCUSSION: Care team members perceive the most value derived from PCPS when pharmacists are able to independently manage medications as care extenders under collaborative agreements with providers.

Implementation of a pharmacist-managed clinic for patients with chronic nonmalignant pain.

PURPOSE: A pharmacist-managed chronic pain clinic (PMCPC) in a primary care setting is described. SUMMARY: As primary care providers (PCPs) may be unprepared or lack time to manage high-risk patients receiving opioids for chronic nonmalignant pain, alternative models of care are needed. The University of Colorado PMCPC is integrated into an internal medicine outpatient clinic. The PMCPC is staffed by 1 clinical pharmacist, with pharmacy students and residents also performing clinic duties. The pharmacy team reviews health records to determine eligibility for PMCPC services and documents referral requests in the electronic health record (EHR); on PCP acceptance of a referral, the pharmacy team assumes primary responsibility for the patient's pain management under a collaborative practice agreement. Using a collaborative drug therapy management (CDTM) protocol, the pharmacy team conducts patient assessments, including an assessment for signs of aberrant drug-taking behaviors; provides initial and ongoing counseling and education; and makes recommendations to the PCP for opioid dosage adjustments and regimen additions and discontinuations. Experience at the clinic to date indicates that the PMCPC model is feasible and accepted by PCPs and patients. CONCLUSION: A PMCPC based in a primary care setting was established to improve the care of patients with chronic nonmalignant pain who are prescribed opioid therapy for a period of 3 months or longer. Clinic patients are referred to the clinic through the EHR and managed by a pharmacist under a CDTM protocol.

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes.

BACKGROUND: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. OBJECTIVES: The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. METHODS: Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients' records was also evaluated. RESULTS: A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%-50%, p = 0.23), elderly men (34%-40%, p = 0.53), and elderly women (60%-74%, p = 0.14), but the change was only significant in young women (42%-70%, p = 0.0045). CONCLUSION: After Food and Drug Administration-mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change.

Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant.

Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

Rational design of a zinc phthalocyanine binding protein.

Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices.

Manipulating cofactor binding thermodynamics in an artificial oxygen transport protein.

We report the mutational analysis of an artificial oxygen transport protein, HP7, which operates via a mechanism akin to that of human neuroglobin and cytoglobin. This protein destabilizes one of two heme-ligating histidine residues by coupling histidine side chain ligation with the burial of three charged glutamate residues on the same helix. Replacement of these glutamate residues with alanine, which is uncharged, increases the affinity of the distal histidine ligand by a factor of 13. Paradoxically, it also decreases heme binding affinity by a factor of 5 in the reduced state and 60 in the oxidized state. Application of a three-state binding model, in which an initial pentacoordinate binding event is followed by a protein conformational change to hexacoordinate, provides insight into the mechanism of this seemingly counterintuitive result: the initial pentacoordinate encounter complex is significantly destabilized by the loss of the glutamate side chains, and the increased affinity for the distal histidine only partially compensates for that. These results point to the importance of considering each oxidation and conformational state in the design of functional artificial proteins.

Medication beliefs and perceived barriers in adolescent renal transplant patients and their parents.

Understanding patient beliefs about medications and perceived barriers is important for optimal medical management. Differentiating adolescent views from parents' perceptions would enhance care by increasing communication about regimens and reducing obstacles. This study explored beliefs about medications and perceived barriers among 40 adolescent kidney transplant patients and their parents. Younger adolescents reported greater concern about medication harmfulness (t(38) = 2.190, p < 0.05) and more barriers, particularly for practical problems including forgetfulness, organization, and coordination (t(38) = 2.049, p < 0.05). Fathers with a lower education reported their children having greater challenges with medications due to taste and size (t(37) = 2.933, p < 0.01). Families with incomes in the low and high levels expressed that their children need more medication reminders (F (2, 35) = 7.815, p < 0.005), and adolescents from lower-income families perceived medication to be more harmful (F (2, 36) = 3.815, p < 0.05). Adolescents expressed challenges with practical aspects of medication taking, whereas parents were more focused on medications being necessary for their health. Adolescent renal patients experience challenges to medication management that may differ from their parents, findings that can help tailor interventions to improve medication management.

Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.

Methylation of histone H3 lysine 27 (H3K27) is a posttranslational modification that is highly correlated with genomic silencing. Here we show that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A. Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Our results suggest a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.

Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein.

Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C(5)HC(2) domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.

Isolation and characterization of histone H3 lysine 4 demethylase-containing complexes.

Histone methylation is involved in the regulation of many cellular processes. In the past 2 years, several histone demethylases including BHC110/LSD1 have been characterized. BHC110, the first known histone lysine demethylase, removes methyl groups from methylated histone H3 lysine 4 and has been found in many multi-protein complexes. Using one-step affinity purification, we have isolated enzymatically active BHC110-containing complexes. Here, we detail the methods used for the isolation and characterization of these histone demethylase complexes from a human stable cell line.

Analysis of Nedd8-associated polypeptides: a model for deciphering the pathway for ubiquitin-like modifications.

Ubiquitin-like proteins modify target proteins, altering their activities or causing them to be slated for degradation. These modifications are used to efficiently regulate key events in the cell. To explore the set of proteins modified by a small ubiquitin-like protein, we have developed a proteomic approach. Affinity purification of an epitope-tagged Nedd8 allowed the identification of the majority of proteins known to be involved with the neddylation pathway. This purification not only isolated the known targets of neddylation but also the constellation of enzymes and complexes known to regulate neddylation and deneddylation, including the COP9 signalosome, Nub1, and enzymes in the neddylation cascade. This purification scheme can be applied to other small ubiquitin-like proteins, especially those with limited protein targets such as the SUMOs (1, 2, and 3), Isg15, or FAT10.

TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing.

MicroRNAs (miRNAs) are generated by a two-step processing pathway to yield RNA molecules of approximately 22 nucleotides that negatively regulate target gene expression at the post-transcriptional level. Primary miRNAs are processed to precursor miRNAs (pre-miRNAs) by the Microprocessor complex. These pre-miRNAs are cleaved by the RNase III Dicer to generate mature miRNAs that direct the RNA-induced silencing complex (RISC) to messenger RNAs with complementary sequence. Here we show that TRBP (the human immunodeficiency virus transactivating response RNA-binding protein), which contains three double-stranded, RNA-binding domains, is an integral component of a Dicer-containing complex. Biochemical analysis of TRBP-containing complexes revealed the association of Dicer-TRBP with Argonaute 2 (Ago2), the catalytic engine of RISC. The physical association of Dicer-TRBP and Ago2 was confirmed after the isolation of the ternary complex using Flag-tagged Ago2 cell lines. In vitro reconstitution assays demonstrated that TRBP is required for the recruitment of Ago2 to the small interfering RNA (siRNA) bound by Dicer. Knockdown of TRBP results in destabilization of Dicer and a consequent loss of miRNA biogenesis. Finally, depletion of the Dicer-TRBP complex via exogenously introduced siRNAs diminished RISC-mediated reporter gene silencing. These results support a role of the Dicer-TRBP complex not only in miRNA processing but also as a platform for RISC assembly.