Comparison of Butorphanol-Azaperone-Medetomidine and Nalbuphine-Medetomidine-Azaperone in Free-Ranging Elk (Cervus canadensis) in Pennsylvania, USA.

Chemical immobilization is commonly used to capture and handle free-ranging elk (Cervus canadensis). Butorphanol-azaperone-medetomidine (BAM) and nalbuphine-medetomidine-azaperone (NalMed-A) are compounded drug combinations that are lower-scheduled in the US than drugs historically used for elk immobilizations. We compared BAM and NalMed-A for immobilization of free-ranging elk using free-darting and Clover trapping. From January 2020 to April 2022, 196 female elk were immobilized in Pennsylvania, USA. We report vital rates, induction and recovery times, and the need for supplemental drugs. We built mixed-effects logistic regression models to describe differences between drug choice based on induction and recovery times, capture method, and individual variation. Several models were competing, including our null model, which suggests that BAM and NalMed-A are comparable based on the parameters we evaluated. Supplemental drug administration was more frequently needed in NalMed-A immobilizations (21.2%) than in BAM immobilizations (9.0%). Overall, we found minor differences between BAM and NalMed-A, both of which appear to be effective for immobilizing elk in both free-darting and Clover trapping scenarios when performing moderately invasive, minimally painful procedures on free-ranging elk.

Sociodemographic Factors Associated with Suicide Outcomes in Transgender and Gender Diverse Young Adults.

OBJECTIVE: Transgender and gender diverse (TGD) populations have a higher prevalence of suicide outcomes compared to cisgender peers. Further, among TGD groups, young adults frequently demonstrate a higher risk compared to other age cohorts. While evidence supports sociodemographic differences in suicide risk, these relationships are not well-established for TGD young adults. METHOD: A secondary data analysis of the young adult (18-24 years) subpopulation of the 2015 U.S. Transgender Survey was conducted. Predicted probabilities of 12-month and lifetime suicide outcomes by gender identity, sexual orientation, race/ethnicity, homelessness, and poverty were estimated comparing fully adjusted models. RESULTS: Gender identity, race/ethnicity, and homelessness were significantly associated with all suicide outcomes. Comparisons of gender identities were significant for all outcomes and varied based on the outcome. American Indian/Alaska Native TGD young adults had the highest predicted probabilities compared to other race/ethnicity groups. Further, having a heterosexual/straight sexual identity was among the lowest predicted probabilities for suicide outcomes and significantly differed from several of the other sexual identities. CONCLUSIONS: Findings underscore the importance of heterogeneity among TGD young adults and the need for intersectional research within this population. Elucidating sociodemographic characteristics that contribute to differential suicide risk is necessary for effective intervention strategies and policy advocacy.

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML.

Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.

IB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells.

Background: Triple negative breast cancer (TNBC), characterized by the lack of three canonical receptors, is unresponsive to commonly used hormonal therapies. One potential TNBC-specific therapeutic target is NQO1, as it is highly expressed in many TNBC patients and lowly expressed in non-cancer tissues. DNA damage induced by NQO1 bioactivatable drugs in combination with Rucaparib-mediated inhibition of PARP1-dependent DNA repair synergistically induces cell death. Methods: To gain a better understanding of the mechanisms behind this synergistic effect, we used global proteomics, phosphoproteomics, and thermal proteome profiling to analyze changes in protein abundance, phosphorylation and protein thermal stability. Results: Very few protein abundance changes resulted from single or dual agent treatment; however, protein phosphorylation and thermal stability were impacted. Histone H2AX was among several proteins identified to have increased phosphorylation when cells were treated with the combination of IB-DNQ and Rucaparib, validating that the drugs induced persistent DNA damage. Thermal proteome profiling revealed destabilization of H2AX following combination treatment, potentially a result of the increase in phosphorylation. Kinase substrate enrichment analysis predicted altered activity for kinases involved in DNA repair and cell cycle following dual agent treatment. Further biophysical analysis of these two processes revealed alterations in SWI/SNF complex association and tubulin / p53 interactions. Conclusions: Our findings that the drugs target DNA repair and cell cycle regulation, canonical cancer treatment targets, in a way that is dependent on increased expression of a protein selectively found to be upregulated in cancers without impacting protein abundance illustrate that multi-omics methodologies are important to gain a deeper understanding of the mechanisms behind treatment induced cancer cell death.

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.

Background: Accumulation of tau in synapses in the early stages of Alzheimer's disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology. Methods: The goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome's hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm. Results: Our results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice. Conclusion: Therefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD.

Pharmacologic Management of Sialorrhea in Neonatal and Pediatric Patients.

Sialorrhea, defined as an excess flow of saliva or excessive secretions, is common in patients with cerebral palsy and other neurologic disorders and is associated with clinical complications such as increased risk of local skin reactions, infections, aspiration, pneumonia, and dehydration. Upon failure of non-pharmacologic measures, clinicians have several noninvasive pharmacologic options available to manage sialorrhea. This review of the literature provides detailed descriptions of medications used, efficacy, safety, and practical considerations for use of non-injectable pharmacologic agents. The literature search included published -human studies in the English language in PubMed and Google Scholar from 1997 to 2022. Relevant citations within articles were also screened. A total of 15 studies representing 719 pediatric patients were included. Glycopyrrolate, atropine, scopolamine, and trihexyphenidyl all have a potential role for sialorrhea management in children; however, glycopyrrolate remains the most studied option with 374 (n = 52.0%) of the 719 patients included in the systematic review receiving this medication. Overall, glycopyrrolate showed similar efficacy but higher tolerability than its comparators in 2 comparative studies and is often considered the first-line agent. Patient-specific (age, route of administration) and medication-specific (dosage formulation, medication strength) considerations must be weighed when initiating a new therapy or switching to another medication upon treatment failure. Owing to the high propensity of adverse events with all agents, clinicians should consider initiating doses at the lower end of the dosage range, as previous studies have noted a dose-dependent relationship.

Grit and postoperative opioid use after total joint arthroplasty.

INTRODUCTION: Perioperative multimodal protocols following total joint replacements have significantly decreased the amount of perioperative and postoperative opioids. Further identification of those requiring more or less opioids through individualisation, may further aid in reducing the amount prescribed. Therefore, the purpose of the study was to evaluate whether a patient's grit, the measurable psychological strength of character to persevere during hardship, measured by postoperative opioid consumption. METHODS: Consecutive patients who had undergone either primary or revision total knee arthroplasty (TKA) or total hip arthroplasty (THA) from February 2019 to August 2020 at our institution logged their opioid use for the first 2 weeks postoperatively, detailing the type, dosage, and number of narcotics they consumed. Those who completed their logs and a grit questionnaire had their average morphine equivalent dose (MED) and grit score calculated. Analysis was then performed to evaluate if any association existed between these 2 variables. RESULTS: There was no correlation between grit score and postoperative opioid consumption in the first 2 weeks following discharge after total joint arthroplasty. A total of 144 patients were eligible to participate and a total of 86 patients met inclusion criteria, 48 patients in the TKA group and 38 in the THA group. Of all patients, 63% were male. The average MED was 95.5 for THAs and 192 for TKAs. The average grit score was 4.23 for THAs and 4.19 for TKAs. CONCLUSIONS: There is not an apparent association between grit score and postoperative opioid consumption in the first 2 weeks after total joint arthroplasty. General psychological resiliency may not be an important predictor of postoperative opioid use with modern postoperative protocols.

Evidence-Based Education on Care of LGBTQ Patients: Improving Knowledge and Attitudes Among Pediatric Nurses.

BACKGROUND: Due to stigma and mistreatment, lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) patients and their families often face barriers to accessing and receiving equitable health care. Pediatric settings are not immune to this health inequity, yet there is limited literature to address it with pediatric nurses. METHOD: An evidence-based education program on the care of LGBTQ patients was delivered electronically to pediatric nurses. Using a pre- and posttest design, knowledge and attitudes regarding care of LGBTQ patients were collected via online questionnaires. RESULTS: Knowledge significantly increased from pre- to posttest (p = .02). Attitudes related to LGBTQ concepts either remained consistently positive or shifted in the positive direction. CONCLUSION: Providing education regarding LGBTQ patients to pediatric nurses can improve related knowledge and attitudes. Expansion of evidence-based LGBTQ education to pediatric nurses is likely to contribute to lessening the health care barriers and inequities faced by these patients and their families. [J Contin Educ Nurs. 2024;55(4):181-186.].

Methionine Restriction Impairs Degradation of a Protein that Aberrantly Engages the Endoplasmic Reticulum Translocon.

Proteins that persistently engage endoplasmic reticulum (ER) translocons are degraded by multiple translocon quality control (TQC) mechanisms. In Saccharomyces cerevisiae , the model translocon-associated protein Deg1 -Sec62 is subject to ER-associated degradation (ERAD) by the Hrd1 ubiquitin ligase and, to a lesser extent, proteolysis mediated by the Ste24 protease. In a recent screen, we identified nine methionine-biosynthetic genes as candidate TQC regulators. Here, we found methionine restriction impairs Hrd1-independent Deg1 -Sec62 degradation. Beyond revealing methionine as a novel regulator of TQC, our results urge caution when working with laboratory yeast strains with auxotrophic mutations, often presumed not to influence cellular processes under investigation.

A scoping review of the concept of resilience among African American women.

Resilience, thriving in the face of adversity, is a critical component of well-being in African American women. However, traditional definitions and approaches to operationalize resilience may not capture race- and gender-related resilience experiences of African American women. A more complete conceptualization of resilience may help facilitate future investigation of the mechanisms through which resilience influences health in this group. Our team conducted a scoping review of the literature published during twenty years, between 2000 and 2019, on resilience and health in African American women. We included a multidisciplinary set of databases (PubMed, CINAHL, PsycINFO, Scopus, Social Work Abstracts, Sociological Abstracts, Academic Search Premier). Using Covidence software a multi-step review process was conducted; 904 abstracts were initially screened for eligibility, 219 full-text studies were screened in stage two, and 22 remaining studies were reviewed for extraction. The studies reviewed revealed limitations of unidimensional approaches to conceptualizing/operationalizing resilience in African American women. The review highlighted culturally-relevant components of resilience including spirituality/religion, strength, survival, active coping, and social support. Findings highlight the importance of operationalizing resilience as a multidimensional construct so it can be optimally included in research designed to investigate the quality of life, cardiovascular risk, and other health outcomes in African American women.

Obtaining Functional Proteomics Insights From Thermal Proteome Profiling Through Optimized Melt Shift Calculation and Statistical Analysis With InflectSSP.

Thermal proteome profiling (TPP) is an invaluable tool for functional proteomics studies that has been shown to discover changes associated with protein-ligand, protein-protein, and protein-RNA interaction dynamics along with changes in protein stability resulting from cellular signaling. The increasing number of reports employing this assay has not been met concomitantly with new approaches leading to advancements in the quality and sensitivity of the corresponding data analysis. The gap between data acquisition and data analysis tools is important to fill as TPP findings have reported subtle melt shift changes related to signaling events such as protein posttranslational modifications. In this study, we have improved the Inflect data analysis pipeline (now referred to as InflectSSP, available at https://CRAN.R-project.org/package=InflectSSP) to increase the sensitivity of detection for both large and subtle changes in the proteome as measured by TPP. Specifically, InflectSSP now has integrated statistical and bioinformatic functions to improve objective functional proteomics findings from the quantitative results obtained from TPP studies through increasing both the sensitivity and specificity of the data analysis pipeline. InflectSSP incorporates calculation of a "melt coefficient" into the pipeline with production of average melt curves for biological replicate studies to aid in identification of proteins with significant melts. To benchmark InflectSSP, we have reanalyzed two previously reported datasets to demonstrate the performance of our publicly available R-based program for TPP data analysis. We report new findings following temporal treatment of human cells with the small molecule thapsigargin that induces the unfolded protein response as a consequence of inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase 2A. InflectSSP analysis of our unfolded protein response study revealed highly reproducible and statistically significant target engagement over a time course of treatment while simultaneously providing new insights into the possible mechanisms of action of the small molecule thapsigargin.

A Cost-Effective Microfluidic Device to Teach the Principles of Electrophoresis and Electroosmosis.

Electrophoresis is integral to analytical and biochemistry experiences in undergraduate education; however, fundamental principles of the method are often taught in upper-level laboratories through hands-on experiences. A laboratory activity is reported that teaches the concepts of electrophoretic mobility and electroosmotic flow. A single reuseable instrument, called a mini-E, costs 37 USD and consists of a DC power supply, a voltmeter, platinum electrodes, and a chip cast in polydimethylsiloxane. This activity uses common reagents costing only 0.02 USD per student. Experiments are devised that allow students to investigate the properties of electrophoretic flow and electroosmotic flow by separating the two commonly used food dyeing agents Brilliant Blue FCF and Allura Red AC in vinegar and in a solution of ammonium hydroxide. A dark-purple mixture of these dyes is separated into red and blue bands that are easily visualized. The migration order of the dyes differs when the separation is performed under conditions of reversed polarity and suppressed electroosmotic flow (vinegar) compared to conditions of normal polarity and active electroosmotic flow (ammonium hydroxide). When delivered to chemistry majors, students had a significant gain in their ability to apply the concepts of electroosmosis and electrophoresis to predict analyte migration. Although this activity targets upper-level chemistry content, it can also be adapted for other laboratory experiences.

Lipid biosynthesis perturbation impairs endoplasmic reticulum-associated degradation.

The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation of Deg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, in Saccharomyces cerevisiae. This screen revealed that INO4 is required for efficient Deg1-Sec62 degradation. INO4 encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis. Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect in ino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases by INO4 deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Loss of INO4 sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.

Associations of depression and anxiety and adolescent telomere length.

BACKGROUND: Telomere length (TL), a biomarker of cellular aging, is influenced by adverse life experiences. Although depression and anxiety are associated with shorter TL in adults, the relationship in younger ages has received little attention. We examined relationships between depression and anxiety diagnoses and symptomatology and TL in adolescence, an important developmental window for early intervention. Sex differences in relationships were also examined. METHODS: Wave 1 survey and TL data from the Adolescent Health and Development in Context study were analyzed (N = 995). Depression and anxiety diagnosis were parent-reported measures categorized as: current diagnosis, prior diagnosis, and never diagnosed (reference category). Depressive symptoms were measured via adolescent-report using nine items from the Center for Epidemiologic Studies-Depression scale, short form. Anxiety symptoms were measured via adolescent-report using eight items from the pediatric anxiety scale obtained from the Patient-Reported Outcomes Measurement Information System. Genomic DNA was isolated from 500 µL saliva via ethanol precipitation. Genomic DNA TL was assessed using monoplexed quantitative polymerase chain reactions. Relative T/S quantities were calculated in accordance with established procedures. Covariates included sociodemographic factors (sex, age, race/ethnicity, caregiver marital status and education level, and household income), pubertal development, and season of collection. Descriptive and multivariable linear regression analyses were conducted, including an examination of sex as a moderator in the relationships between depression, anxiety, and TL. RESULTS: In multivariable analysis, adolescents with a current depression diagnosis (b = -0.26, p < .05), but not a prior diagnosis (b =0.05, p > .05) had shorter TL than those who were never diagnosed; higher depressive symptom scores were associated with shorter TL (b = -0.12, p < .05). No significant associations were found between anxiety diagnosis and TL; however, higher anxiety symptom scores were associated with shorter TL (b = -0.14, p < .01). Sex did not significantly moderate any of the relationships between depression, anxiety and TL. CONCLUSIONS: Depression and anxiety were associated with shorter TL in this diverse community sample of adolescents and the findings highlight the potential for impaired mental health to contribute to cellular senescence as early as adolescence. Prospective research on the long-term effect of depression and anxiety occurring earlier in the life span on TL over time is needed, including examination of potential mechanisms that may accelerate or buffer the negative effects of impaired mental health on TL.

Metagenomic Sequencing of Two Cultures Grown on Chemically Deconstructed Plastic Products.

We report the metagenome sequences of two microbial cultures that were grown with chemically deconstructed plastic products as their sole carbon source. These metagenomes will provide insights into the metabolic capabilities of cultures grown on deconstructed plastics and can serve as a starting point for the identification of novel plastic degradation mechanisms.

Lewis-Acid-Catalyzed Oxa-Michael Addition to Give α-Diazo-ß-alkoxy Carbonyls and Tetrahydro-3H-furo[3,4-c]pyrazoles.

The conjugate addition of alcohols to vinyl diazonium ions formed via Zn(OTf)2-catalysis gives α-diazo-ß-alkoxy carbonyls. The diazo group is retained in this reaction, and this process is an efficient way to couple a reactive partner to the diazo fragment. As an example, we disclose that addition of allyl alcohols provides tetrahydro-3H-furo[3,4-c]pyrazoles via an addition/cycloaddition sequence. This two-step sequence provides good yields and good diastereoselectivity of these sterically hindered pyrazoline scaffolds with up to three quaternary centers and four stereogenic centers. These products can be elaborated to cyclopropane-fused tetrahydrofurans upon liberation of nitrogen. The reaction conditions are mild, operationally simple, and avoid the use of expensive transition metal catalysts.

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.

Accumulation of tau in synapses in Alzheimer’s disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of pathology through synaptically connected neurons. Synaptic loss correlates with a decline in cognition, providing an opportunity to investigate strategies to target synaptic tau to rescue or prevent cognitive decline. One of the promising synaptic targets is the 5-HT4 receptor present post-synaptically in the brain areas involved in the memory processes. 5-HT4R activation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tauopathy. The goal of this study was to investigate the impact of stimulation of 5-HT4R in tauopathy mice. Our results show that 5-HT4R agonism led to reduced tauopathy and synaptic tau and correlated with increased proteasome activity and improved cognitive functioning in PS19 mice. Thus, stimulation of 5-HT4R offers a promising therapy to rescue synapses from toxic synaptic tau.

Tumor Suppressor p53 Down-Regulates Programmed Cell Death Protein 4 (PDCD4) Expression.

The programmed cell death protein 4 (PDCD4), a well-known tumor suppressor, inhibits translation initiation and cap-dependent translation by inhibiting the helicase activity of EIF4A. The EIF4A tends to target mRNAs with a structured 5'-UTR. In addition, PDCD4 can also prevent tumorigenesis by inhibiting tumor promoter-induced neoplastic transformation, and studies indicate that PDCD4 binding to certain mRNAs inhibits those mRNAs' translation. A previous study demonstrated that PDCD4 inhibits the translation of p53 mRNA and that treatment with DNA-damaging agents down-regulates PDCD4 expression but activates p53 expression. The study further demonstrated that treatment with DNA-damaging agents resulted in the downregulation of PDCD4 expression and an increase in p53 expression, suggesting a potential mechanism by which p53 regulates the expression of PDCD4. However, whether p53 directly regulates PDCD4 remains unknown. Herein, we demonstrate for the first time that p53 regulates PDCD4 expression. Firstly, we found that overexpression of p53 in p53-null cells (H1299 and Saos2 cells) decreased the PDCD4 protein level. Secondly, p53 decreased PDCD4 promoter activity in gene reporter assays. Moreover, we demonstrated that mutations in p53 (R273H: contact hotspot mutation, and R175H: conformational hotspot mutation) abolished p53-mediated PDCD4 repression. Furthermore, mutations in the DNA-binding domain, but not in the C-terminal regulatory domain, of p53 disrupted p53-mediated PDCD4 repression. Finally, the C-terminal regulatory domain truncation study showed that the region between aa374 and aa370 is critical for p53-mediated PDCD4 repression. Taken together, our results suggest that p53 functions as a novel regulator of PDCD4, and the relationship between p53 and PDCD4 may be involved in tumor development and progression.

Exogenous testosterone administration is associated with differential neural response to unfamiliar peer's and own caregiver's voice in transgender adolescents.

Changes in gonadal hormones during puberty are thought to potentiate adolescents' social re-orientation away from caregivers and towards peers. This study investigated the effect of testosterone on neural processing of emotional (vocal) stimuli by unfamiliar peers vs. parents, in transgender boys receiving exogenous testosterone as a gender-affirming hormone (GAH+) or not (GAH-). During fMRI, youth heard angry and happy vocal expressions spoken by their caregiver and an unfamiliar teenager. Youth also self-reported on closeness with friends and parents. Whole-brain analyses (controlling for age) revealed that GAH+ youth showed blunted neural response to caregivers' angry voices-and heightened response to unfamiliar teenage angry voices-in the anterior cingulate cortex. This pattern was reversed in GAH- youth, who also showed greater response to happy unfamiliar teenager vs. happy caregiver voices in this region. Blunted ACC response to angry caregiver voices-a pattern characteristic of GAH+ youth-was associated with greater relative closeness with friends over parents, which could index more "advanced" social re-orientation. Consistent with models of adolescent neurodevelopment, increases in testosterone during adolescence may shift the valuation of caregiver vs. peer emotional cues in a brain region associated with processing affective information.

Visualizing chemical space networks with RDKit and NetworkX.

This article demonstrates how to create Chemical Space Networks (CSNs) using a Python RDKit and NetworkX workflow. CSNs are a type of network visualization that depict compounds as nodes connected by edges, defined as a pairwise relationship such as a 2D fingerprint similarity value. A step by step approach is presented for creating two different CSNs in this manuscript, one based on RDKit 2D fingerprint Tanimoto similarity values, and another based on maximum common substructure similarity values. Several different CSN visualization features are included in the tutorial including methods to represent nodes with color based on bioactivity attribute value, edges with different line styles based on similarity value, as well as replacing the circle nodes with 2D structure depictions. Finally, some common network property and analysis calculations are presented including the clustering coefficient, degree assortativity, and modularity. All code is provided in the form of Jupyter Notebooks and is available on GitHub with a permissive BSD-3 open-source license: https://github.com/vfscalfani/CSN_tutorial.