Faculty Bibliography

Psychedelics, substances with a long history of cultural and medicinal use, are experiencing a resurgence in clinical research, particularly in psychiatry. Despite their classification as Schedule I drugs, recent studies suggest therapeutic potential, particularly in treating refractory depression. With chronic pain representing a major health concern and with few non-opioid treatment options available, psychedelics are being explored as alternative treatment modalities. The National Institutes of Health (NIH) now funds psychedelic research, marking a shift from previous decades of limited funding. However, ethical considerations loom large. Vulnerable populations, such as those with chronic pain that impairs their autonomy, require careful consideration by researchers of risks and benefits. Additionally, researchers and interested entities must navigate complex regulatory landscapes involving the United States Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) when considering pursuing possible research. Furthermore, transparent collaboration among stakeholders-patients, researchers, and regulatory bodies-is crucial for participant safety and successful research. Although a number of ethical approaches can be taken, we posit that stakeholders consider utilizing principal-based research ethics, comprised of the principles of autonomy, beneficence, justice, and nonmaleficence, to guide the process. Ultimately, balancing therapeutic promise with ethical integrity is paramount. Careful planning, collaboration, and adherence to ethical principles can increase the likelihood that psychedelic research in chronic pain management progresses responsibly, offering hope for patients while safeguarding their well-being.

Anxiety disorders are highly comorbid with sleep disturbance and have also been associated with deficits in emotion regulation, the ability to control and express emotions. However, the extent to which specific dimensions of sleep disturbance and emotion regulation are associated with anxiety diagnosis is not well-explored. This study examined dimensions of emotion regulation and sleep disturbance that may predict greater likelihood of anxiety diagnosis using novel machine learning techniques. Participants (Mean(SD) age= 28.6(11.3) years, 62.7% female) with primary anxiety disorders (n = 257), including generalized anxiety disorder (n = 122) and social anxiety disorder (n = 135), and healthy controls (n = 89) completed the Difficulties in Emotion Regulation Scale and Pittsburgh Sleep Quality Index. A conditional inference tree was fit to classify likelihood of current anxiety diagnosis based on predictors. The best model fit included 4 split nodes and 5 terminal nodes. Worse scores on two emotion regulation subscales, strategies directed to manage negative emotions and nonacceptance of negative emotions, were the best predictors of current anxiety diagnosis (99.3% probability of diagnosis). For those with better emotion regulation, poor sleep quality and worse daytime functioning due to sleep were important predictors of anxiety diagnosis. Good emotion regulation and non-disturbed sleep predicted high likelihood of being a non-psychiatric control (88.2%). Limitations include cross-sectional design precluding designating directionality of effects of sleep and emotion regulation on anxiety onset; limited sample size; and self-reported sleep. Facets of emotion regulation and sleep disturbance may be important early targets for brief intervention for anxiety disorders.

Clinical, neuroimaging and genomics evidence have increasingly underscored a degree of overlap between autism and attention-deficit/hyperactivity disorder (ADHD). This study explores the specific contribution of their core symptoms to shared biology in a sample of N=166 verbal children (6-12 years) with rigorously-established primary diagnoses of either autism or ADHD (without autism). We investigated the associations between inter-individual differences in clinician-based dimensional measures of autism and ADHD symptoms and whole-brain low motion intrinsic functional connectivity (iFC). Additionally, we explored their linked gene expression patterns in silico. Whole-brain multivariate distance matrix regression revealed a transdiagnostic association between autism severity and iFC of two nodes: the middle frontal gyrus of the frontoparietal network and posterior cingulate cortex of the default mode network. Across children, the greater the iFC between these nodes, the more severe the autism symptoms, even after controlling for ADHD symptoms. Results from segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC interactions for autism symptom severity across diagnoses. No statistically significant brain-behavior relationships were observed for ADHD symptoms. Genetic enrichment analyses of the iFC maps associated with autism symptoms implicated genes known to: (i) have greater rate of variance in autism and ADHD, and (ii) be involved in neuron projection, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. Overall, these findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined phenomena to shared presentations at the macroscale circuit- and genomic-levels among children with diagnoses of autism and ADHD.

Our genome is not made of naked DNA but a fiber (chromatin) composed of DNA and proteins packaged into our chromosomes. The basic building block of chromatin is the nucleosome, which has two copies of each of the proteins called histones (H2A, H2B, H3, and H4) wrapped by 146 base pairs of DNA. Regions of our genetic material are found between the more open (euchromatin) and more compact (heterochromatin) regions of the genome that can be variably accessible to the underlying genes. Furthermore, post-translational modifications (PTMs) on histones, such as on H3, are critical for regulating chromatin accessibility and gene expression. While site-specific antibodies were the tool of choice for histone PTM analysis in the early days (pre-2000s), enter Don Hunt changing the histone PTM field forever. Don's clever thinking brought new innovative mass spectrometry-based approaches to the epigenetics field. His lab's effort led to the discovery of many new histone modifications and methods to facilitate the detection and quantification of histone PTMs, which are still considered state of the art in the proteomics field today. Due to Don's pioneering work in this area, many labs have been able to jump into the epigenetics field and "Hunt" down their own histone targets. A walkthrough of those early histone years in the Hunt Lab is described by three of us who were fortunate enough to be at the right place, at the right time.

Inflammation has been demonstrated to negatively impact patients in the peri-ACS period. This narrative review outlines the inflammatory response in ACS, highlighting the role of the NLRP3 inflammasome pathway following acute plaque rupture and coronary intervention and its potential as a pharmacologic target. RECENT: nvestigators have leveraged medications targeting the NLRP3 inflammasome currently used for other inflammatory pathologies, including colchicine, tocilizumab and anakinra. Investigation into these drugs in the peri-ACS period has yielded varying results, with the most encouraging findings in ACS patients treated with tocilizumab. More conflicting data exists for the role of colchicine and anakinra, with many studies limited in their power to detect clinical outcomes and heterogeneity in their patient populations and endpoints. Despite conflicting data, the NLRP3 remains an attractive therapeutic target in the peri-ACS period. Further investigation is required to prove benefit and safety with large clinical trials adequately powered for clinical outcomes.

Methamphetamine (MA) dependence leads to severe physical and psychological issues. Current treatments, including psychosocial therapies and residential rehabilitation, face limitations such as high relapse rates, cost, and accessibility issues. As a result, there is an urgent need for novel approaches to treat MA dependence that are effective, affordable, and accessible to patients. Psilocybin, the active component in numerous mushrooms of the Psilocybe genus, has shown potential for enhancing psychotherapy for various addiction and mental health issues due to its effects on perception, cognition, and affect. Psilocybin-assisted psychotherapy (PAT) has demonstrated initial safety and efficacy in treating alcohol, cocaine, and nicotine dependence. The case presented here describes a 36-year-old transwoman and daily MA user, who participated in a single-arm open-label clinical trial assessing feasibility and safety of PAT for MA dependence at St. Vincent's Hospital, Sydney. Following inpatient withdrawal management and one session of psilocybin-assisted therapy, she experienced significant cognitive and emotional shifts and sustained MA abstinence. She reported improved mental health over 3 months following treatment completion. She also noted increased self-esteem, mindfulness, and distress tolerance. This study suggests that PAT (following inpatient MA withdrawal management) may offer a scalable, safe, and effective approach for treating MA dependence. However, further research is required to confirm the generalisability and efficacy of PAT for broader populations of people using MA. It is encouraging that this participant, a daily MA user, showed improvements in mood and cognition, in addition to abstinence from MA.

UNLABELLED: TRIAL REGISTRATION/UNASSIGNED:clinicaltrials.gov Identifier: NCT01179568.

Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D-binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis. Here, we develop monobodies with nanomolar binding affinities against the D-SH2 domain of the leukemic tyrosine kinase BCR::ABL1. Two crystal structures of heterochiral monobody-SH2 complexes reveal targeting of the pY binding pocket by an unconventional binding mode. We then prepare potent D-monobodies by either ligating two chemically synthesized D-peptides or by self-assembly without ligation. Their proper folding and stability are determined and high-affinity binding to the L-target is shown. D-monobodies are protease-resistant, show long-term plasma stability, inhibit BCR::ABL1 kinase activity and bind BCR::ABL1 in cell lysates and permeabilized cells. Hence, we demonstrate that functional D-monobodies can be developed readily. Our work represents an important step towards possible future therapeutic use of D-monobodies when combined with emerging methods to enable cytoplasmic delivery of monobodies.

Protein post-translational modifications play a vital role in various cellular events essential for maintaining cellular physiology and homeostasis. In cancer cells, aberrant post-translational modifications such as glycosylation, acetylation, and phosphorylation on proteins can result in the generation of antigenic peptide variants presented in complex with MHC molecules. These modified peptides add to the class of tumorspecific antigens and offer promising avenues for targeted anti- cancer therapies. In this review, we focus on the role of phosphorylated peptides (p-peptides) in cancer immunity. We discuss the mechanisms by which the phosphorylated moiety modifies the structural features and binding properties of p-peptides with MHC, compared to their non-phosphorylated counterparts. Additionally, we review recent work on how the HLA-B*07-specific p-peptide, pMLL_747-755, interacts with its cognate TCR. Altogether, p-peptides are emerging as a novel class of tumor-specific antigens, expanding the range of targets in cancer immunotherapy.