Predicting the Hallucinogenic Potential of Molecules Using Artificial Intelligence.

The development of new drugs addressing serious mental health and other disorders should avoid the psychedelic experience. Analogs of psychedelic drugs can have clinical utility and are termed "psychoplastogens". These represent promising candidates for treating opioid use disorder to reduce drug dependence, with rarely reported serious adverse effects. This drug abuse cessation is linked to the induction of neuritogenesis and increased neuroplasticity, a hallmark of psychedelic molecules, such as lysergic acid diethylamine. Some, but not all psychoplastogens may act through the G-protein coupled receptor (GPCR) 5HT2A whereas others may display very different polypharmacology making prediction of hallucinogenic potential challenging. In the process of developing tools to help design new psychoplastogens, we have used artificial intelligence in the form of machine learning classification models for predicting psychedelic effects using a published in vitro data set from PsychLight (support vector classification (SVC), area under the curve (AUC) 0.74) and in vivo human data derived from books from Shulgin and Shulgin (SVC, AUC, 0.72) with nested five-fold cross validation. We have also explored conformal predictors with ECFP6 and electrostatic descriptors in an effort to optimize them. These models have been used to predict known 5HT2A agonists to assess their potential to act as psychedelics and induce hallucinations for PsychLight (SVC, AUC 0.97) and Shulgin and Shulgin (random forest, AUC 0.71). We have tested these models with head twitch data from the mouse. This predictive capability is desirable to reliably design new psychoplastogens that lack in vivo hallucinogenic potential and help assess existing and future molecules for this potential. These efforts also provide useful insights into understanding the psychedelic structure activity relationship.

Outcomes of Deep Hypothermic Circulatory Arrest for Descending and Thoracoabdominal Aneurysm Repair.

OBJECTIVE: Deep hypothermic circulatory arrest (DHCA) in patients undergoing descending (DTAA) or thoracoabdominal aortic aneurysm (TAAA) repair is associated with increased morbidity and mortality. We present our outcomes after open DTAA and TAAA repair with and without DHCA. METHODS: From 1999 to 2022, 81 (38.8%) patients undergoing DTAA or TAAA repair required DHCA because proximal cross-clamping was not feasible or aneurysmal pathology extended into the arch and 128 (61.2%) patients required only distal bypass. Because of intrinsic pathological differences in patients requiring DHCA, confidence intervals were used to compare groups in lieu of formal hypothesis tests. RESULTS: DHCA patients had more chronic dissections (64.2% vs 43.8%, 95% CI for difference: 6% - 35%) and higher BMIs (29.5 ± 6.8 vs 27.2 ± 6.6, CI: 26% - 421%). More non-DHCA patients had medial degeneration (9.9% vs 31.3%, CI: -33% - -7%). There were 10 (12.4%) in-hospital deaths for the DHCA and 10 (7.8%) for the non-DHCA group (CI: -5% - 14%). Survival at 10 years was 52.6% (CI: 42.1%-65.7%) for the non-DHCA group and 48.3% (CI: 40.3%-57.9%) for the DHCA group. The only meaningful differences in postoperative outcomes were ICU (5.5 days vs 6 days, CI: 12%-410%) and hospital stay (19 days vs 12 days, CI: 74%-470%), which were longer in the DHCA group. CONCLUSIONS: Despite longer ICU and hospital length of stays, selective use of DHCA is safe and effective with comparable morbidity and mortality to non-DHCA in open DTAA and TAAA repair.

De Novo Design of Peptide Binders to Conformationally Diverse Targets with Contrastive Language Modeling.

Designing binders to target undruggable proteins presents a formidable challenge in drug discovery, requiring innovative approaches to overcome the lack of putative binding sites. Recently, generative models have been trained to design binding proteins via three-dimensional structures of target proteins, but as a result, struggle to design binders to disordered or conformationally unstable targets. In this work, we provide a generalizable algorithmic framework to design short, target-binding linear peptides, requiring only the amino acid sequence of the target protein. To do this, we propose a process to generate naturalistic peptide candidates through Gaussian perturbation of the peptidic latent space of the ESM-2 protein language model, and subsequently screen these novel linear sequences for target-selective interaction activity via a CLIP-based contrastive learning architecture. By integrating these generative and discriminative steps, we create a Pep tide Pr ioritization via CLIP ( PepPrCLIP ) pipeline and validate highly-ranked, target-specific peptides experimentally, both as inhibitory peptides and as fusions to E3 ubiquitin ligase domains, demonstrating functionally potent binding and degradation of conformationally diverse protein targets in vitro . Overall, our design strategy provides a modular toolkit for designing short binding linear peptides to any target protein without the reliance on stable and ordered tertiary structure, enabling generation of programmable modulators to undruggable and disordered proteins such as transcription factors and fusion oncoproteins.

Presynaptic Rac1 in the hippocampus selectively regulates working memory.

One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms.

Does a broad-spectrum cannabidiol supplement improve performance in a 10-min cycle ergometer performance-test?

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid which has been proposed to possess anti-inflammatory and analgesic properties. Given the potential for perceptions of pain to limit exercise performance, the aim of the present study was to investigate if 3 weeks of daily CBD supplementation (150 mg day-1) improved performance in a 10-min performance-trial on a cycle ergometer. In a randomized, double-blind and placebo-controlled study, 22 healthy participants (n = 11 male and n = 11 female) completed two 10-min performance trials on a WattBike cycle ergometer interspersed with a 3-week supplementation period. Supplementation involved either 150 mg day-1 oral CBD or 150 mg day-1 of a visually identical placebo (PLA). During trials, ratings of perceived exertion (RPE [6-20]), heart rate (HR) and blood lactate (BLa) were collected every 2 min. Mean power (W) was also taken throughout the exercise at each time point. All data were analyzed using two-way ANOVAs. There were no significant differences (P > 0.05) between CBD or PLA groups for mean power (W) during the 10-min performance trial. There were also no significant differences (P > 0.05) in any of the physiological or perceptual parameters (HR, BLa and RPE) between conditions. Three weeks supplementation of a broad-spectrum CBD supplement did not improve performance via any change in RPE during a 10-min time trial on a cycle ergometer, and as such, this evidence does not support the claim that broad-spectrum CBD supplements could be performance-enhancing in this exercise modality.

CD28 co-stimulation: novel insights and applications in cancer immunotherapy.

Substantial progress in understanding T cell signalling, particularly with respect to T cell co-receptors such as the co-stimulatory receptor CD28, has been made in recent years. This knowledge has been instrumental in the development of innovative immunotherapies for patients with cancer, including immune checkpoint blockade antibodies, adoptive cell therapies, tumour-targeted immunostimulatory antibodies, and immunostimulatory small-molecule drugs that regulate T cell activation. Following the failed clinical trial of a CD28 superagonist antibody in 2006, targeted CD28 agonism has re-emerged as a technologically viable and clinically promising strategy for cancer immunotherapy. In this Review, we explore recent insights into the molecular functions and regulation of CD28. We describe how CD28 is central to the success of current cancer immunotherapies and examine how new questions arising from studies of CD28 as a clinical target have enhanced our understanding of its biological role and may guide the development of future therapeutic strategies in oncology.

Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates.

Introduction: Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.

Shoulder Motion Overestimated by Mallet Scores.

BACKGROUND: Brachial plexus birth injuries (BPBI) occur in up 0.4 to 4.6 per 1000 live births. Weakness about the shoulder and development of glenohumeral joint contractures are common sequalae of BPBI. Shoulder function in children with BPBI is frequently assessed using the modified Mallet classification to evaluate upper extremity motion deficits. The purpose of this study was to assess the accuracy of the abduction, external rotation, and hand-to-mouth Mallet classification scores in children with BPBI using motion capture. METHODS: A retrospective study of 107 children with BPBI who underwent motion capture assessment and Mallet scores on the same date were reviewed. Motion capture measurements were used to calculate humerothoracic elevation and external rotation joint angles in the abduction/hand-to-mouth and external rotation positions, respectively. The humerothoracic joint angles were converted to the corresponding Mallet scores. Discrepancies between the Mallet scores determined by clinicians and those determined by motion capture were assessed. RESULTS: For abduction, 24.3% of Mallet scores were misclassified during clinical examination. Of the misclassified scores, 22 were overestimated by 1 point and 4 were underestimated by 1 point compared with motion capture. For external rotation, 72.9% of Mallet scores were misclassified during clinical examination. Only 5 patients had an HT elevation that was less than 40 degrees, with 4 of them (80%) having a Mallet hand-to-mouth score of 4. There were no differences in proportion of patients with HT elevation less than 40 degrees who had a Mallet score of 4 or a Mallet score less than 4. CONCLUSIONS: There was better agreement in global abduction Mallet scores compared with external rotation and hand-to-mouth Mallet scores. This difference was likely due to the complex compensatory strategies that patients employ while performing external rotation and hand-to-mouth positions. The inaccuracy of the clinically determined Mallet scores is alarming given that they are frequently utilized to assist with surgical indications and are commonly used as outcome measures. LEVEL OF EVIDENCE: Level IV Case series.

Complete genome sequence of Microbacterium foliorum phage Curie, a podovirus isolated from soil in Spokane, Washington.

Bacteriophage Curie is a podovirus that infects Microbacterium foliorum. The Curie genome spans 16,810 bp, has 90 bp terminal inverted repeats, and includes 23 protein-coding genes. Its genome architecture resembles phage PineapplePizza and other phi29-like phages. Together, Curie and PineapplePizza form a new actinobacteriophage Cluster GI.

Brief Report: Relationships Between Caregiver-Reported Externalizing and Internalizing Behaviors and the Modified Checklist for Autism in Toddlers.

PURPOSE: Early detection and intervention are associated with improved outcomes for autistic children. Thus, it is important to understand factors influencing early screening tools designed to detect autism. This study examined the relationship between caregiver-reported emotional and behavioral symptoms and children's scores on a commonly used autism screening questionnaire, the Modified Checklist for Autism in Toddlers-Revised with Follow-Up (M-CHAT-R/F). METHODS: Toddlers were recruited from four primary care clinics between 2018 and 2021. Their caregivers completed the M-CHAT-R/F as well as the Child Behavior Checklist (CBCL), a well-validated, normed measure of emotional and behavioral functioning. Correlational and group analyses were evaluated to examine relationships between CBCL scales and M-CHAT-R/F scores. RESULTS: 1765 toddlers were recruited for the study. CBCL scores for the internalizing, externalizing, autism, ADHD, and anxiety scales were all modestly positively correlated with M-CHAT-R/F scores. Compared to toddlers with elevated autism scale scores only, toddlers with elevations in both autism and ADHD/externalizing scales had higher M-CHAT-R/F scores. In contrast, no significant difference in scores were found between toddlers with elevated autism scale scores only compared to those with elevated scores on both autism and internalizing scales. CONCLUSION: Findings suggest that, for children with elevated autism behaviors, the presence of externalizing symptoms, including ADHD-related concerns, is associated with elevated scores on the M-CHAT-R/F. In contrast, internalizing symptoms did not show an association with elevated M-CHAT-R/F scores among toddlers with elevated autism-related behaviors. Interpretation of the M-CHAT-R/F should include consideration of co-occurring psychiatric conditions, especially externalizing conditions such as ADHD.

A Criteria to Reduce Interhospital Transfer of Traumatic Brain Injuries in Greater East Texas.

BACKGROUND: Traumatic brain injury (TBI) due to single-level falls (SLF) are frequent and often require interhospital transfer. This retrospective cohort study aimed to assess the safety of a criteria for non-transfer among a subset of TBI patients who could be observed at their local hospital, vs mandatory transfer to a level 1 trauma center (L1TC). METHODS: We conducted a 7-year review of patients with TBI due to SLF at a rural L1TC. Patients were classified as transfer/non-transfer according to the Brain Injuries in Greater East Texas (BIGTEX) criteria. The primary outcome measure was the occurrence of a critical event defined as deteriorating repeat head computed tomography (CT) scan or neurological status, neurosurgical intervention, or death. RESULTS: Of the 689 included patients, 63 (9.1%) were classified as non-transfer. Although there were 4 cases with a neurological change and one with a head CT change among the non-transfer group, there were no neurosurgical procedures or deaths. The Cox Proportional Hazard model showed a near 3-fold increased risk of experiencing a critical event if classified as a non-transfer. The multivariable regression model showed patients with an Abbreviated Injury Scale (AIS) of 3 was twice as likely to experience a critical event, with an AIS of 4, three times, and 3 times more likely to be classified to transfer. DISCUSSION: The BIGTEX criteria identify a subset of patients who can safely be observed at their local hospital. To confirm the safety and efficacy of this transfer criteria recommendation, a prospective study is warranted.

Assessing Pediatric Resident Needs in Grief and Bereavement Education.

CONTEXT: Pediatric residents care for dying children during training. Few educational efforts focus on helping trainees better understand their own grief process and the supports available to them and their patients' families. OBJECTIVES: This work aims to assess pediatric residents' needs and preferences for content included in a curriculum on grief and bereavement. METHODS: Pediatric residents, at a single institution, completed an electronic survey in Spring 2023 on how they cope with patient deaths and their preferences on content in a proposed grief and bereavement curriculum. RESULTS: The survey was emailed to 165 current or recent trainees; 71 surveys were fully completed (43% response rate). Most respondents (63/71, 89%) indicated that a formalized bereavement curriculum for pediatric residents is important. The resources most frequently utilized by residents following a pediatric death included peer support (59/71, 83%), attending a debrief coordinated by residency leadership or the supportive care division (38/71, 54%), and reading a patient's obituary (23/71, 32%). The most desired content areas were institutional services provided to bereaved families (66/71, 93%), unique aspects of healthcare professional grief (58/71, 82%), and experiences of bereaved families hearing from providers after their child's death (56/71, 79%). CONCLUSION: Pediatric residents indicate a strong desire for structured curricula on grief and bereavement focusing on resources that exist for families, approaches to grieving as a healthcare professional, and better understanding the experiences of bereaved families. These data may inform educators on priorities in training and support of pediatric residents on grief and bereavement.

Exploring perceptions of inpatient hospital attire in children with cancer.

BACKGROUND: Attire bolsters identity, self-expression, and comfort. Hospital gowns are known to be distressing in adults. Attitudes of children with cancer toward hospital attire remain uninvestigated and may be a modifiable factor in overall well-being. METHODS: A 39-item mixed methods survey evaluated perceptions of patient attire in children with cancer. Children aged 7-18 years were recruited at an academic medical center. Data analysis included simple statistics and thematic analysis. RESULTS: Forty children with cancer receiving oncologic care participated. Participants' mean age was 12.4 (SD = 3.0, range = 7-17) years, and 25 (62%) were male. Quantitative data revealed 81% of participants preferred their own attire when admitted to the hospital, feeling more comfortable in such when well (91%) or sick (75%). They did not feel like they "must" wear a gown when admitted (60%) and did not want to be asked about preferred inpatient attire (63%). Thematic analysis revealed that children had strong negative views of gowns and preferred to wear their own attire in the hospital, which provided physical and emotional comfort. Children worried wearing their own clothing could impede their care. CONCLUSION: Children with cancer prefer wearing their own clothes in the hospital for physical and emotional comfort. They are willing to wear gowns for ease of care; however, they do not want to arbitrate when they need to make that choice. Providers may ease distress by considering a child's own clothes as default hospital attire with instructions for when a gown is necessary for good clinical care.

Acute toxicity of the fungicide captan to honey bees and mixed evidence for synergism with the insecticide thiamethoxam.

Honey bees are commonly co-exposed to pesticides during crop pollination, including the fungicide captan and neonicotinoid insecticide thiamethoxam. We assessed the impact of exposure to these two pesticides individually and in combination, at a range of field-realistic doses. In laboratory assays, mortality of larvae treated with captan was 80-90% greater than controls, dose-independent, and similar to mortality from the lowest dose of thiamethoxam. There was evidence of synergism (i.e., a non-additive response) from captan-thiamethoxam co-exposure at the highest dose of thiamethoxam, but not at lower doses. In the field, we exposed whole colonies to the lowest doses used in the laboratory. Exposure to captan and thiamethoxam individually and in combination resulted in minimal impacts on population growth or colony mortality, and there was no evidence of synergism or antagonism. These results suggest captan and thiamethoxam are each acutely toxic to immature honey bees, but whole colonies can potentially compensate for detrimental effects, at least at the low doses used in our field trial, or that methodological differences of the field experiment impacted results (e.g., dilution of treatments with natural pollen). If compensation occurred, further work is needed to assess how it occurred, potentially via increased queen egg laying, and whether short-term compensation leads to long-term costs. Further work is also needed for other crop pollinators that lack the social detoxification capabilities of honey bee colonies and may be less resilient to pesticides.

Harmonization of Longitudinal Diffusion Tensor Imaging Data of the Pediatric Cervical and Thoracic Spinal Cord at 3T Using Longitudinal ComBat.

Diffusion tensor imaging (DTI) of the spinal cord has been extensively used to identify biomarkers for spinal cord pathology. Previously, the longitudinal ComBat (longComBat) technique was examined to reduce scanner effects in multi-site, multi-scanner spinal cord DTI data. This study aimed to assess its effectiveness on longitudinal scans using a single-scanner pediatric dataset, including healthy and spinal cord injury (SCI) subjects. Two identical datasets were collected from 42 healthy and 27 SCI subjects with a 2-hour interval between scans on a 3T Siemens MRI scanner. Axial DTI images of the entire cervical and thoracic spinal cord were obtained, and various average diffusion tensor metrics (FA, MD, RD, & AD) were measured at each vertebral level. Pearson correlation and intraclass correlation coefficients were used to evaluate inter- and intra-subject agreement pre- and post-harmonization. Minimal improvement in agreement was observed with the mean square residual (MSR) model, while the restricted maximum likelihood estimator (REML) model showed reduced intra-subject agreement in all the tensor metrics. The significant variability between longitudinal DTI scans within a single scanner was likely due to physiological motion rather than scanner effects. Post-harmonization using the longComBat MSR model showed limited improvement in agreement.

NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.

CTL recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells but also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM-1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes (TIL) and long-term survival of melanoma patients. Using MART-1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM-1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior costimulatory effects of DNAM-1 over CD28 involved enhanced TCR signaling, CTL killer function and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in the antigen specificity and selectivity of killer function. In addition, the elevation of NKR-Ligand expression on cancer cells by chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAA. Our data help to explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.

Decoupling Fluorous Protein Coatings Yield Heat-Stable and Intrinsically Sterile Bioformulations.

Thermal inactivation is a major bottleneck to the scalable production, storage, and transportation of protein-based reagents and therapies. Failures in temperature control both compromise protein bioactivity and increase the risk of microorganismal contamination. Herein, we report the rational design of fluorochemical additives that promiscuously bind to and coat the surfaces of proteins to enable their stable dispersion within fluorous solvents. By replacing traditional aqueous liquids with fluorinated media, this strategy conformationally rigidifies proteins to preserve their structure and function at extreme temperatures (≥90 °C). We show that fluorous protein formulations resist contamination by bacterial, fungal, and viral pathogens, which require aqueous environments for survival, and display equivalent serum bioavailability to standard saline samples in animal models. Importantly, by designing dispersants that decouple from the protein surface in physiologic solutions, we deliver a fluorochemical formulation that does not alter the pharmacologic function or safety profile of the functionalized protein in vivo. As a result, this nonaqueous protein storage paradigm is poised to open technological opportunities in the design of shelf-stable protein reagents and biopharmaceuticals.

Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium.

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.

Changes in Shoulder Rotation Based on Elevation in Children With Brachial Plexus Birth Injury.

PURPOSE: Lack of shoulder external rotation is common in children with brachial plexus birth injuries. Development of glenohumeral (GH) dysplasia is associated with progressive loss of passive external rotation. Some authors recommend measuring external rotation with the arm adducted, whereas others recommend measurement with the arm in 90° of abduction. The purpose of this study was to compare active and passive external rotation and internal rotation measured in adduction versus abduction. METHODS: Fifteen children with brachial plexus birth injuries held their affected arms in maximal external and internal rotation with the arm adducted and the arm at approximately 90° of abduction. Active and passive rotations were measured with three-dimensional motion capture. Scapulothoracic (ST) internal/external rotation and GH internal/external rotation joint angles were calculated and compared using multivariable, one-way repeated measures analyses of variance. RESULTS: There were no significant differences for active or passive ST rotation in external rotation in adduction versus abduction. Glenohumeral external rotation was significantly increased with the arm in abduction compared with adduction both actively and passively. There were no differences in ST rotation in active versus passive conditions, but all GH rotations were significantly greater passively. CONCLUSIONS: Shoulder internal/external rotation in abduction and adduction is not interchangeable. Comprehensive assessment of shoulder external and internal rotation should include both adduction and abduction. CLINICAL RELEVANCE: For children with brachial plexus birth injuries, both active and passive GH external rotations were greater in abduction. Therefore, early GH joint dysplasia may be missed if GH external rotation is measured in abduction. Additionally, consistency in arm position is important for comparison over time. The entire ST rotation capacity was used to perform maximal internal and external rotation, but the entire passive GH range of motion was not actively used. This highlights an area for potential surgical intervention to improve motion.

Pro-survival signaling regulates lipophagy essential for multiple myeloma resistance to stress-induced death.

Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.