Human cytokine and coronavirus nucleocapsid protein interactivity using large-scale virtual screens.

Understanding the interactions between SARS-CoV-2 and the human immune system is paramount to the characterization of novel variants as the virus co-evolves with the human host. In this study, we employed state-of-the-art molecular docking tools to conduct large-scale virtual screens, predicting the binding affinities between 64 human cytokines against 17 nucleocapsid proteins from six betacoronaviruses. Our comprehensive in silico analyses reveal specific changes in cytokine-nucleocapsid protein interactions, shedding light on potential modulators of the host immune response during infection. These findings offer valuable insights into the molecular mechanisms underlying viral pathogenesis and may guide the future development of targeted interventions. This manuscript serves as insight into the comparison of deep learning based AlphaFold2-Multimer and the semi-physicochemical based HADDOCK for protein-protein docking. We show the two methods are complementary in their predictive capabilities. We also introduce a novel algorithm for rapidly assessing the binding interface of protein-protein docks using graph edit distance: graph-based interface residue assessment function (GIRAF). The high-performance computational framework presented here will not only aid in accelerating the discovery of effective interventions against emerging viral threats, but extend to other applications of high throughput protein-protein screens.

Exploring trauma and wellbeing of people who use drugs after witnessing overdose: A qualitative study.

BACKGROUND: The national overdose crisis is often quantified by overdose deaths, but understanding the traumatic impact for those who witness and respond to overdoses can help elucidate mental health needs and opportunities for intervention for this population. Many who respond to overdoses are people who use drugs. This study adds to the literature on how people who use drugs qualitatively experience trauma resulting from witnessing and responding to overdose, through the lens of the Trauma-Informed Theory of Individual Health Behavior. METHODS: We conducted 60-min semi-structured, in-depth phone interviews. Participants were recruited from six states and Washington, DC in March-April 2022. Participants included 17 individuals who witnessed overdose(s) during the COVID-19 pandemic. The interview guide was shaped by theories of trauma. The codebook was developed using a priori codes from the interview guide; inductive codes were added during content analysis. Transcripts were coded using ATLAS.ti. RESULTS: A vast majority reported trauma from witnessing overdoses. Participants reported that the severity of trauma varied by contextual factors such as the closeness of the relationship to the person overdosing or whether the event was their first experience witnessing an overdose. Participants often described symptoms of trauma including rumination, guilt, and hypervigilance. Some reported normalization of witnessing overdoses due to how common overdoses were, while some acknowledged overdoses will never be "normal." The impacts of witnessing overdose on drug use behaviors varied from riskier substance use to increased motivation for treatment and safer drug use practices. CONCLUSION: Recognizing the traumatic impact of witnessed overdoses is key to effectively addressing the full range of sequelae of the overdose crisis. Trauma-informed approaches should be central for service providers when they approach this subject with clients, with awareness of how normalization can reduce help-seeking behaviors and the need for psychological aftercare. We found increased motivation for behavior change after witnessing, which presents opportunity for intervention.

Continuous Epidural Hydromorphone Infusion for Post-Cesarean Delivery Analgesia in a Patient on Methadone Maintenance Therapy: A Case Report.

The prevalence of opioid use disorder (OUD) in the United States has more than quadrupled over the past two decades. This patient population presents a number of challenges to clinicians, including difficult pain management after surgical procedures due to the development of opioid tolerance. Significantly greater opioid consumption and pain scores after cesarean delivery have been reported in patients with OUD compared to other obstetric patients. A multi-modal analgesic regimen is generally recommended, but there are few well-established pain management strategies after cesarean delivery specific to patients with OUD. We present the case of a patient with OUD maintained on daily methadone that received a continuous epidural hydromorphone infusion for post-cesarean analgesia, a technique not previously reported in obstetric patients and only rarely described for patients undergoing other surgical procedures. The patient received epidural anesthesia for cesarean delivery, and after surgery, the epidural catheter was left in place for the epidural hydromorphone infusion, initiated at 140 mcg/hr and continued for approximately 40 hrs. This strategy reduced her average daily oral opioid consumption by 97%, reduced self-reported pain scores, shortened the length of hospitalization and improved ability to ambulate compared to her previous cesarean delivery. The use of continuous epidural hydromorphone infusion was effective in this case, and this analgesic technique may also be applicable to other types of surgical procedures with the potential for significant post-operative pain, particularly in patients with OUD.

Post-Cesarean Delivery Analgesic Outcomes in Patients Maintained on Methadone and Buprenorphine: A Retrospective Investigation.

BACKGROUND: Despite the increasing prevalence of opioid use disorder (OUD) in pregnant women, there are limited studies on their anesthesia care and analgesic outcomes after cesarean delivery (CD). METHODS: Patients with OUD on either buprenorphine or methadone maintenance therapy who underwent CD at our institution from 2011 to 2018 were identified. Anesthetic details and analgesic outcomes, including daily opioid consumption and pain scores, were compared between patients maintained on buprenorphine and methadone. Analgesic outcomes were also evaluated according to anesthetic type (neuraxial or general anesthesia) and daily buprenorphine/methadone dose to determine if these factors impacted pain after delivery. RESULTS: A total of 146 patients were included (buprenorphine n=99 (67.8%), methadone n=47 (32.2%)). Among all patients: 74% had spinal/CSE, 15% epidural, and 11% general anesthesia. Anesthesia types were similar among buprenorphine and methadone patients. For spinal anesthetics, intrathecal fentanyl (median 15 µg) and morphine (median 100 µg) were commonly given (97.2% and 96.3%, respectively), and dosed similarly between groups. Among epidural anesthetics, epidural morphine (median 2 mg) was commonly administered (90.9%), while fentanyl (median 100 µg) was less common (54.5%). Buprenorphine and methadone groups consumed similar amounts of oxycodone equivalents per 24 hours of hospitalization (80.6 vs 76.3 mg; p=0.694) and had similar peak pain scores (8.3 vs 8.0; p=0.518). Daily methadone dose correlated weakly with opioid consumption (R=0.3; p=0.03), although buprenorphine dose did not correlate with opioid consumption or pain scores. General anesthesia correlated with greater oxycodone consumption in the first 24 hours (median 156.1 vs 91.7 mg; p=0.004) and greater IV PCA use (63% vs 7%; p<0.001) compared to neuraxial anesthesia. CONCLUSION: Patients on buprenorphine and methadone had similar high opioid consumption and pain scores after CD. The anesthetic details and analgesic outcomes reported in this investigation may serve as a useful reference for future prospective investigations and aid in the clinical care of these patients.

Neurobiology of Addiction.

Drugs of abuse can cause changes in the brain leading to addiction. Current scientific focus has been on how these drugs interact with the brain and the changes they cause, how those changes affect human behavior and how they may last beyond termination of drug use. Compulsiveness in seeking the drug, impulsiveness in consuming the drug, and negative affect when the drug is withheld are characteristic of addiction. Each of these characteristics has a root in neurobiology and understanding their mechanisms helps us to understand addiction and see potential targets for treatment.

Compliant threads maximize spider silk connection strength and toughness.

Millions of years of evolution have adapted spider webs to achieve a range of functionalities, including the well-known capture of prey, with efficient use of material. One feature that has escaped extensive investigation is the silk-on-silk connection joints within spider webs, particularly from a structural mechanics perspective. We report a joint theoretical and computational analysis of an idealized silk-on-silk fibre junction. By modifying the theory of multiple peeling, we quantitatively compare the performance of the system while systematically increasing the rigidity of the anchor thread, by both scaling the stress-strain response and the introduction of an applied pre-strain. The results of our study indicate that compliance is a virtue-the more extensible the anchorage, the tougher and stronger the connection becomes. In consideration of the theoretical model, in comparison with rigid substrates, a compliant anchorage enormously increases the effective adhesion strength (work required to detach), independent of the adhered thread itself, attributed to a nonlinear alignment between thread and anchor (contact peeling angle). The results can direct novel engineering design principles to achieve possible load transfer from compliant fibre-to-fibre anchorages, be they silk-on-silk or another, as-yet undeveloped, system.