Citations

Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism’s lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.

Cytotoxic T cells produce the cytokine interferon-γ (IFN-γ). We sought to determine whether IFN-γ directly kills target cells and found that T cells used IFN-γ to kill murine melanoma cells lacking the kinases TBK1 and IKKε. In the absence of both kinases, IFN-γ induced the production of TNF receptor 1 (TNFR1) and the sensor Z-DNA binding protein 1 (ZBP1) in the tumor cells to stimulate receptor-interacting protein kinase 1 (RIPK1)–dependent apoptosis in a cell-autonomous manner. IFN-γ also enhanced the activation of nuclear factor κB (NF-κB) signaling in a TNFR1-dependent manner in cells deficient in both TBK1 and IKKε. Because IFN-γ–induced apoptosis occurred in a transcription-dependent manner with slow kinetics, STAT1 and NF-κB cooperated to activate the expression of inflammatory genes in the dying cells. Thus, IFN-γ–induced cell death was accompanied by an inflammatory signature in the absence of TBK1 and IKKε. TBK1 and IKKε not only mediated the induction of type I IFN but also inhibited RIPK1-dependent death and NF-κB–dependent inflammation. Therefore, we propose that these kinases may have gained these intertwined functions so that cells infected by pathogens that produce antagonists of TBK1 and IKKε are eliminated by IFN-γ–secreting T cells in an inflammatory manner to compensate for the inhibition of type I IFN production.

Objectives Comparing clinical outcomes after cardiopulmonary bypass with hemodsorption (HA) versus cardiopulmonary bypass without HA in patients undergoing cardiac surgery in terms of mortality and major complications. Methods PubMed, Scopus, and Web of Science databases were searched for relevant randomized control trials (RCTs) that compared postoperative clinical outcomes between patients receiving intraoperative HA with cardiopulmonary bypass versus patients receiving cardiopulmonary bypass without intraoperative HA in cardiac surgery. Results Sixteen RCTs with 851 patients (433 in the HA group and 418 in the control group), were included in our meta-analysis. Our meta-analysis found no significant differences between the intraoperative HA group and the control group in patients undergoing cardiac surgery in terms of 30-days/in-hospital mortality, new-onset atrial fibrillation, stroke or cerebrovascular events, postoperative delirium, renal failure/acute kidney injury, need for renal replacement, postoperative liver dysfunction, thrombocytopenia, bleeding, volume of blood loss, pneumonia, sepsis, respiratory insufficiency, duration of postoperative ventilation, distributive/septic shock, pericardial tamponade, need for extracorporeal membrane oxygenation (ECMO) support, sequential organ failure assessment (SOFA) score at ICU admission, plasma-free hemoglobin levels, and fibrinogen levels. However, the pooled analysis showed a significant association between HA and decreased albumin at ICU admission (MD = − 0.28, 95% CI [0.55 to 0.01], p -value = 0.04), decreased length of ICU stay (MD = −0.66, 95% CI [−1.24 to 0.08], p -value = 0.03), and decreased length of hospital stay (MD = −0.99, 95% CI [−1.88 to −0.10], p -value = 0.03). Conclusion Our findings suggest that there is not enough evidence to endorse the role of routine intraoperative HA during cardiopulmonary bypass in improving clinical outcomes after cardiac surgery. Factors such as patient risk profile, procedure complexity, and cost implications should be taken into account when considering this adjunct therapy.

Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103 + dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR + dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage–dependent and EMT-inducing effects of ATR ATR promotes metastasis and immunosuppression through EMT process

Importance Opioid prescribing has decreased in the US for more than a decade. However, less is known about how prescribing trends differ by prescriber specialty and separately for short-term and long-term opioid prescribing for which the indications, clinical decision-making, and potential for harm vary substantially. Objective To characterize opioid analgesic prescribing trends in the US between January 1, 2010, and December 31, 2024, by prescriber specialty, analyzing short-term and long-term opioid use episodes separately. Design, Setting, and Participants This cross-sectional study used administrative claims data for commercially insured and Medicare Advantage patients (aged ≥65 years and <65 years with long-term disability) with at least 90 days of enrollment in medical and prescription coverage. Statistical analysis was performed from May 2025 to September 2025. Main Outcomes and Measures Prescribing volume, daily dose, and prescription duration. Results The study identified 110 288 218 opioid fills by 14 959 612 patients during the 15-year study period. Among opioid fills, 59.4% were attributed to female patients; the median (IQR) age at opioid fill was 61 (50-71) years. From 2010 to 2024, decreases in opioid prescribing were greater for long-term than short-term opioid use episodes (eg, commercial cohort: 81.3% reduction [from 33.2 fills per 100-person years in 2010 to 6.2 in 2024] and 74.6% reduction [from 36.2 fills per 100-person years in 2010 to 9.2 in 2024]), respectively. The proportion of all opioid fills written by primary care clinicians decreased (eg, Medicare Advantage with disability cohort: from 52.2% to 47.2%), whereas those written by pain medicine specialists increased (eg, Medicare Advantage with disability cohort: from 17.1% to 25.7%). Distinct trends for short-term and long-term opioid use episodes were observed in prescription characteristics, such as daily dose and duration. Conclusions and Relevance In this cross-sectional study of opioid prescribing trends in the US between 2010 and 2024, decreases in prescribing were greatest in long-term opioid use episodes, and prescribing was increasingly concentrated among pain medicine specialists. These findings suggest the need to balance reductions in opioid prescribing with provision of nonopioid pain treatments and raise concerns about access to care for patients taking opioids for chronic pain management.

Importance High-quality evidence guiding opioid prescribing decisions for acute pain across common diagnoses is lacking. Objective To describe pain trajectories and patterns of opioid and nonopioid treatment use among individuals who were offered opioids for the treatment of acute pain. Design, Setting, and Participants This was a prospective cohort study of patients recruited from 5 US health systems between September 2020 and March 2023 in emergency departments (EDs), primary care clinics, dental practices, or after cesarean delivery or knee replacement. Eligible patients were opioid-naive adults aged 18 years or older at all study sites, as well as adolescents aged 15 to17 years undergoing impacted molar extraction at 1 site, who were offered an opioid prescription for acute pain. Analysis was conducted April 2023 through February 2026. Exposure Offer of a prescription for an opioid analgesic. Main Outcomes and Measures Time to pain resolution (3 consecutive reports of no pain), patterns of opioid and nonopioid treatment use, and opioid-related adverse effects, ascertained from digital questionnaires. Results Among 1708 enrolled patients (median age, 38 years [IQR, 28-52 years]; 615 [36.0%] reporting race or ethnicity underrepresented in studies of acute pain management) followed up for 180 days, 915 (53.6%) were recruited in EDs, 307 (18.0%) in primary or urgent care, 263 (15.4%) in dental settings, and 223 (13.1%) in inpatient settings. Pain sources included dental (302 patients [17.7%]), trauma or injury (302 [17.7%]), obstetric (176 [10.3%]), musculoskeletal (131 [7.7%]), and low back (100 [5.9%]). Among 1502 patients reporting pain level at least once, median time to pain resolution irrespective of the treatment approach was 20 days (IQR, 8-88 days), with longer durations for surgical pain (74 days [IQR, 30 days to not reached]) and low back pain (69 days [IQR, 18 days to not reached]). The median time to opioid discontinuation among 1189 patients (69.6%) who reported any opioid use was 7 days (IQR, 2-31 days); an estimated 10.0% (95% CI, 7.7%-12.7%) of patients used opioids for at least 90 days, with higher rates in people reporting frequent pain before enrollment. Of 1482 patients (86.8%) completing at least 1 survey during the first 2 weeks of follow-up, 1153 (77.8%) reported using any opioids and 1287 (86.8%) reported using acetaminophen or ibuprofen. Among 619 (52.1%) patients with any opioid use who reported the dose of opioids taken in the first 15 days, daily doses were low (median, 10 [IQR, 5-15] morphine milligram equivalents). Most respondents reported leftover opioids (657 of 982 responding [66.9%]). Conclusions and Relevance In this cohort study of opioid-naive patients with acute pain, opioid use was generally low dose and of short duration, although some patients reported prolonged opioid use; most reported achieving pain resolution within 3 weeks, with longer times for surgical and low back pain. The findings suggest current guidelines for multimodal treatment and for short-duration opioid prescriptions if needed will serve many but not all patients, and treatment should be tailored to address individual patients’ needs.

Importance Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative. Objective To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms. Design, Setting, and Participants This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October 28, 2020; chose ISDO or RRSO; and were followed up for 24 months. The analysis was performed on November 13, 2024. Interventions Participant-selected RRSO or ISDO. Main Outcomes and Measures Changes in sexual function and menopausal symptoms from baseline to 6, 12, and 24 months. Inverse probability weighting was applied to achieve covariate balance across groups. Results The analytic sample included 334 female participants (mean [95% CI] age at consent, 39.2 [38.7-.9.7] years) who underwent RRSO (n = 165) or ISDO (n = 169) and completed 6-month questionnaires. Significantly more participants experienced clinically meaningful worsening of sexual function at 6 months compared with baseline after RRSO vs ISDO (33.1% [39 of 118] vs 16.8% [17 of 101], respectively; odds ratio, 2.00 [95% CI, 1.20-3.35]) and at 12 months (39.2% [38 of 97] vs 18.3% [17 of 93], respectively; odds ratio, 1.69 [95% CI, 1.09-2.63]). This finding was no longer significant at 24 months. When restricted to the RRSO group who took hormone replacement therapy, there was no significant worsening of total sexual function scores or menopausal symptoms compared with baseline. No interval ovarian cancers were reported. Conclusions and Relevance This nonrandomized clinical trial comparing RRSO with ISDO found that ISDO was less likely to impair sexual function, which addresses an important barrier to surgical prevention in high-risk patients in premenopause. After RRSO, use of hormone replacement therapy mitigated menopausal symptoms and prevented decline in sexual function. More information is needed about the safety of ISDO. Trial Registration ClinicalTrials.gov Identifier: NCT02760849

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Abstract Background Alzheimer’s disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform. Methods A series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences’ NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis. Results AD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models. Conclusion This work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.