Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs optimized for therapeutic efficacy. Designed Trikines co-activated pSTAT5 and pSTAT3 signatures distinct from any natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. An IL-2-based-Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without toxicity. Unexpectedly, an IL-10-based Trikine induced immune infiltration into poorly immunogenic tumors, showing striking efficacy in small cell lung cancer and pancreatic cancer models. Trikines obviate the need for cell engineering to customize STAT signatures for immunotherapy.

Label-free and effective sorting of red and white blood cells based on their physical properties is crucial for subsequent single-cell analysis or immune cell engineering applications. However, cell sorting relying on the physical effects of one single physical property remains highly challenging. This paper proposes a cell sorting method based on a focused traveling surface acoustic wave (FTSAW)-based acoustofluidic chip, which leverages the ability of FTSAW acoustofluidics to comprehensively respond to multiple physical characteristics of cells (e.g., size, density, morphology, and deformability), and furthermore allows for precise setting of the action area range and adjustment of the action intensity. In experiments, a pair of focused interdigital transducers (FIDTs, characteristic frequency: 128.6 MHz) on the substrate of lithium niobate and a typical microchannel structure (single-side sheath flow focusing followed by bifurcated sorting, i.e., "two streams merging into one and then splitting into two") were designed and fabricated. Parameter optimization experiments for separation and sorting were conducted on 3 μm and 5 μm polystyrene (PS) beads, as well as red and white blood cell samples after sheath flow focusing. The results indicate that the FTSAW-based acoustofluidic chip enabled white blood cell sorting with high purity (∼90%) and high biological viability (∼98%). This study demonstrates the potential of the FTSAW-based acoustofluidic chip for cell sorting. Owing to its easy integration and advantages (non-contact operation, no sieve pore clogging, broad compatibility with cell culture media), it is expected to serve as a key pre-processing technology in microfluidic systems for single-cell analysis or cell engineering.

Neighbourhood socioeconomic disadvantage correlates with cardiovascular disease risk. However, its relationship with subclinical atherosclerosis from childhood to midlife is not well-defined. We examined whether cumulative neighbourhood disadvantage is associated with carotid artery plaques, a measure of subclinical atherosclerosis. We analysed data from 1998 participants in the Cardiovascular Risk in Young Finns Study, a cohort followed from childhood (mean age 10.7years in 1980) to adulthood (mean age 48.6years in 2018-2020). Neighbourhood disadvantage was derived from national grid-based socioeconomic data and computed cumulatively across the life course. The number of carotid artery plaques (mean plaque count) was assessed by standardized ultrasound imaging. Multivariable Poisson regression models were used to evaluate the associations. Mediation analyses were used to assessed the role of ideal cardiovascular health (CVH) metrics. Higher cumulative neighbourhood disadvantage from childhood to mid-adulthood was associated with a 1.24-fold increase in mean plaque count for every 1 standard deviation increase in cumulative disadvantage. This relationship persisted after controlling for parental carotid artery plaques, polygenic coronary artery disease risk score, and Framingham risk score. The association was partially explained by ideal CVH metrics, particularly smoking and blood pressure, which collectively accounted for almost half of the association. Long-term exposure to neighbourhood socioeconomic disadvantage beginning in childhood is associated with subclinical atherosclerosis in midlife, independently of achieved socioeconomic position. These findings highlight the importance of cumulative socioeconomic environments across the life course and suggest that behavioural risk factors may partly explain observed neighbourhood-level associations with atherosclerosis.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Mechanisms driving aggressive meningiomas remain poorly understood. Given the pivotal role of the immune microenvironment in tumor progression, we developed a comprehensive atlas of the meningioma microenvironment, with a view toward identifying modifiable opportunities. The immune microenvironment of 2,727 meningiomas was profiled using orthogonal methodologies, including 24 with mass cytometry, 24 single-cell RNAseq, 1,437 bulk RNAseq, 1,125 DNA methylation, 117 multiplex immunofluorescence, as well as that of 5 paired peripheral blood samples and 10 human meninges. Patient-derived organotypic tumor spheroids (PDOTS) were established to assess the effect of STING stimulation combined with anti-PD-1 treatment. We revealed a rich immune infiltration in meningioma, among the highest across 34 human cancer types (n = 12,188). Macrophages predominated in meningioma microenvironment, in contrast to the lymphoid dominance of peripheral blood, with meninges exhibiting an intermediate immune profile between meningiomas and peripheral blood. Cellular states and phenotypes of both immune and tumor cells shifted during tumor progression, with aggressive meningiomas possessing earlier-stage, immunosuppressive immune cells and proliferative tumor cells. Using ex vivo meningioma PDOTS, we demonstrated inducible responses to STING activation, marked by elevated cytokine release, which were synergistic when combined with PD-1 blockade. These findings offer an extensive resource on the cellular heterogeneity of the meningioma microenvironment and provide a framework for rational therapeutic modeling and strategy development.

Practicing CBT skills outside of therapy sessions is a core component of effective treatment, yet meaningful engagement can be difficult during periods of elevated psychological distress. Smartphone-based ecological momentary interventions (EMIs) offer a promising approach to support real-time skill use, but most research has focused on frequency rather than quality of engagement. This study examined the quality of CBT skills practice in a 28-day smartphone-based EMI following inpatient discharge and explored its associations with internal context and intervention effectiveness. Twenty-three adults hospitalized for suicidal thoughts and behaviors participated, selecting and practicing one of three guided CBT skills exercises (Mindful Emotional Awareness, Countering Emotional Behavior, or Cognitive Flexibility) up to three times daily. A structured coding system was used to rate the completeness and relevance of 945 total exercises (0-2 scale). Quality varied primarily within individuals and was lower during moments of high suicidal intent and urge. When combining across all skills, quality was not associated with proximal change. However, higher-quality Countering Emotional Behavior practice predicted greater reductions in suicidal intent, and higher-quality Countering Emotional Behavior and Cognitive Flexibility practice predicted greater reductions in anger. These findings suggest that momentary distress can impact engagement quality, and that the short-term impact of skills practice may depend on both the specific CBT strategy and type of distress targeted. Understanding and enhancing engagement quality is a key step toward optimizing mobile interventions for individuals in the midst of psychological distress.