Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

Gene therapy for adenosine deaminase severe combined immune deficiency-An unexpected journey of four decades.

Severe combined immune deficiency due to adenosine deaminase deficiency (ADA SCID) is an inborn error of immunity with pan-lymphopenia, due to accumulated cytotoxic adenine metabolites. ADA SCID has been treated using gene therapy with a normal human ADA gene added to autologous hematopoietic stem cells (HSC) for over 30 years. Iterative improvements in vector design, HSC processing methods, and clinical HSC transplant procedures have led nearly all ADA SCID gene therapy patients to achieve consistently beneficial immune restoration with stable engraftment of ADA gene-corrected HSC over the duration of observation (as long as 20 years). One gene therapy for ADA SCID is approved by the European Medicines Agency (EMA) in the European Union (EU) and another is being advanced to licensure in the U.S. and U.K. Despite the clear-cut benefits and safety of this curative gene and cell therapy, it remains challenging to achieve sustained availability and access, especially for rare disorders like ADA SCID.

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit ß-type 10 in six infants with SCID-Omenn syndrome.

Mutations in proteasome ß-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome ß2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired ß-ring/ß-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

Synergistic regulation at physiological, transcriptional and metabolic levels in tomato plants subjected to a combination of salt and heat stress.

With global warming and climate change, abiotic stresses often simultaneously occur. Combined salt and heat stress was a common phenomenon that was severe, particularly in arid/semi-arid lands. We aimed to reveal the systematic responsive mechanisms of tomato genotypes with different salt/heat susceptibilities to combined salt and heat stress. Morphological and physiological responses of salt-tolerant/sensitive and heat-tolerant/sensitive tomatoes at control, heat, salt and combined stress were investigated. Based on leaf Fv /Fm and H2 O2 content, samples from tolerant genotype at the four treatments for 36 h were taken for transcriptomics and metabolomics. We found that plant height, dry weight and net photosynthetic rate decreased while leaf Na+ concentration increased in all four genotypes under salt and combined stress than control. Changes in physiological indicators such as photosynthetic parameters and defence enzyme activities in tomato under combined stress were regulated by the expression of relevant genes and the accumulation of key metabolites. We screened five key pathways in tomato responding to a combination of salt and heat stress, such as oxidative phosphorylation (map00190). Synergistic regulation at morphological, physiological, transcriptional and metabolic levels in tomato plants was induced by combined stress. Heat stress was considered as a dominant stressor for tomato plants under the current combined stress. The oxidative phosphorylation pathway played a key role in tomato in response to combined stress, where tapped key genes (e.g. alternative oxidase, Aox1a) need further functional analysis. Our study will provide a valuable resource important for studying stress combination and improving tomato tolerance.

Yield reduction caused by elevated temperatures and high nitrogen fertilization is mitigated by SP6A overexpression in potato (Solanum tuberosum L.).

Potatoes (Solanum tuberosum L.) are a fundamental staple for millions of people worldwide. They provide essential amino acids, vitamins, and starch - a vital component of the human diet, providing energy and serving as a source of fiber. Unfortunately, global warming is posing a severe threat to this crop, leading to significant yield losses, and thereby endangering global food security. Industrial agriculture traditionally relies on excessive nitrogen (N) fertilization to boost yields. However, it remains uncertain whether this is effective in combating heat-related yield losses of potato. Therefore, our study aimed to investigate the combinatory effects of heat stress and N fertilization on potato tuber formation. We demonstrate that N levels and heat significantly impact tuber development. The combination of high N and heat delays tuberization, while N deficiency initiates early tuberization, likely through starvation-induced signals, independent of SELF-PRUNING 6A (SP6A), a critical regulator of tuberization. We also found that high N levels in combination with heat reduce tuber yield rather than improve it. However, our study revealed that SP6A overexpression can promote tuberization under these inhibiting conditions. By utilizing the excess of N for accumulating tuber biomass, SP6A overexpressing plants exhibit a shift in biomass distribution towards the tubers. This results in an increased yield compared to wild-type plants. Our results highlight the role of SP6A overexpression as a viable strategy for ensuring stable potato yields in the face of global warming. As such, our findings provide insights into the complex factors impacting potato crop productivity.

Metabolomics and transcriptomics analysis revealed the response mechanism of alfalfa to combined cold and saline-alkali stress.

Cold and saline-alkali stress are frequently encountered by plants, and they often occur simultaneously in saline-alkali soils at mid to high latitudes, constraining forage crop distribution and production. However, the mechanisms by which forage crops respond to the combination of cold and saline-alkali stress remain unknown. Alfalfa (Medicago sativa L.) is one of the most essential forage grasses in the world. In this study, we analyzed the complex response mechanisms of two alfalfa species (Zhaodong [ZD] and Blue Moon [BM]) to combined cold and saline-alkali stress using multi-omics. The results revealed that ZD had a greater ability to tolerate combined stress than BM. The tricarboxylic acid cycles of the two varieties responded positively to the combined stress, with ZD accumulating more sugars, amino acids, and jasmonic acid. The gene expression and flavonoid content of the flavonoid biosynthesis pathway were significantly different between the two varieties. Weighted gene co-expression network analysis and co-expression network analysis based on RNA-Seq data suggested that the MsMYB12 gene may respond to combined stress by regulating the flavonoid biosynthesis pathway. MsMYB12 can directly bind to the promoter of MsFLS13 and promote its expression. Moreover, MsFLS13 overexpression can enhance flavonol accumulation and antioxidant capacity, which can improve combined stress tolerance. These findings provide new insights into improving alfalfa resistance to combined cold and saline-alkali stress, showing that flavonoids are essential for plant resistance to combined stresses, and provide theoretical guidance for future breeding programs.

PDR9 allelic variation and MYB63 modulate nutrient-dependent coumarin homeostasis in Arabidopsis.

Plant roots release phytochemicals into the soil environment to influence nutrient availability and uptake. Arabidopsis thaliana roots release phenylpropanoid coumarins in response to iron (Fe) deficiency, likely to enhance Fe uptake and improve plant health. This response requires sufficient phosphorus (P) in the root environment. Nonetheless, the regulatory interplay influencing coumarin production under varying availabilities of Fe and P is not known. Through genome-wide association studies, we have pinpointed the influence of the ABC transporter G family member, PDR9, on coumarin accumulation and trafficking (homeostasis) under combined Fe and P deficiency. We show that genetic variation in the promoter of PDR9 regulates its expression in a manner associated with coumarin production. Furthermore, we find that MYB63 transcription factor controls dedicated coumarin production by regulating both COUMARIN SYNTHASE (COSY) and FERULOYL-CoA 6'-HYDROXYLASE 1 (F6'H1) expression while orchestrating secretion through PDR9 genes under Fe and P combined deficiency. This integrated approach illuminates the intricate connections between nutrient signaling pathways in coumarin response mechanisms.

Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis.

Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.

Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA.

Analysis of the methylome of tumor cell-free deoxyribonucleic acid (DNA; cfDNA) has emerged as a powerful non-invasive technique for cancer subtyping and prognosis. However, its application is frequently hampered by the quality and total cfDNA yield. Here, we demonstrate the feasibility of very low-input cfDNA for whole-methylome and copy-number profiling studies using enzymatic conversion of unmethylated cysteines [enzymatic methyl-seq (EM-seq)] to better preserve DNA integrity. We created a model for predicting genomic subtyping and prognosis with high accuracy. We validated our tool by comparing whole-genome CpG sequencing with in situ cohorts generated with bisulfite conversion and array hybridization, demonstrating that, despite the different techniques and sample origins, information on cfDNA methylation is comparable with in situ cohorts. Our findings support use of liquid biopsy followed by EM-seq to assess methylome of cancer patients, enabling validation in external cohorts. This advance is particularly relevant for rare cancers like neuroblastomas where liquid-biopsy volume is restricted by ethical regulations in pediatric patients.

Turning cold tumors hot: from molecular mechanisms to clinical applications.

Immune checkpoint blockade (ICB) therapies have achieved clinical benefit, but most 'immune-cold' solid tumors are not responsive. The diversity of immune evasion mechanisms remains a key obstacle in turning nonresponsive 'cold' tumors into responsive 'hot' ones. Therefore, exploring the mechanisms of such transitions and tumor immunotyping can provide significant insights into designing effective therapeutic strategies against cancer. Here, we focus on the latest advances regarding local and systemic regulatory mechanisms of immune responses in cold and hot tumors. We also highlight the necessity for tumor immunotyping through the assessment of multiple immunological variables using various diagnostic techniques and biomarkers. Finally, we discuss the challenges and potential clinical applications of immunophenotyping to turn cold tumors hot, which may further guide combined immunotherapies.

The genome of Haberlea rhodopensis provides insights into the mechanisms for tolerance to multiple extreme environments.

Haberlea rhodopensis, a resurrection species, is the only plant known to be able to survive multiple extreme environments, including desiccation, freezing temperatures, and long-term darkness. However, the molecular mechanisms underlying tolerance to these stresses are poorly studied. Here, we present a high-quality genome of Haberlea and found that ~ 23.55% of the 44,306 genes are orphan. Comparative genomics analysis identified 89 significantly expanded gene families, of which 25 were specific to Haberlea. Moreover, we demonstrated that Haberlea preserves its resurrection potential even in prolonged complete darkness. Transcriptome profiling of plants subjected to desiccation, darkness, and low temperatures revealed both common and specific footprints of these stresses, and their combinations. For example, PROTEIN PHOSPHATASE 2C (PP2C) genes were substantially induced in all stress combinations, while PHYTOCHROME INTERACTING FACTOR 1 (PIF1) and GROWTH RESPONSE FACTOR 4 (GRF4) were induced only in darkness. Additionally, 733 genes with unknown functions and three genes encoding transcription factors specific to Haberlea were specifically induced/repressed upon combination of stresses, rendering them attractive targets for future functional studies. The study provides a comprehensive understanding of the genomic architecture and reports details of the mechanisms of multi-stress tolerance of this resurrection species that will aid in developing strategies that allow crops to survive extreme and multiple abiotic stresses.

Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia.

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.

Aerobic, resistance, or combined exercise training and cardiovascular risk profile in overweight or obese adults: the CardioRACE trial.

BACKGROUND AND AIMS: To determine the comparative efficacy of resistance, aerobic, and combined resistance plus aerobic exercise on cardiovascular disease (CVD) risk profile. METHODS: This randomized controlled trial enrolled 406 adults aged 35-70 years with overweight or obesity and elevated blood pressure. Participants were randomly assigned to resistance (n = 102), aerobic (n = 101), combined resistance plus aerobic exercise (n = 101), or no-exercise control (n = 102). All exercise participants were prescribed 1 h of time-matched supervised exercise (the combination group with 30 min of each resistance and aerobic exercise) three times per week for 1 year. The primary outcome was the change from baseline to 1 year in the standardized composite Z-score of four well-established CVD risk factors: systolic blood pressure, low-density lipoprotein (LDL) cholesterol, fasting glucose, and per cent body fat. RESULTS: Among 406 participants (53% women), 381 (94%) completed 1-year follow-up. Compared with the control group, the composite Z-score decreased at 1 year, which indicates improved CVD risk profile, in the aerobic {mean difference, -0.15 [95% confidence interval (CI): -0.27 to -0.04]; P = .01} and combination [mean difference, -0.16 (95% CI: -0.27 to -0.04); P = .009] groups, but not in the resistance [mean difference, -0.02 (95% CI: -0.14 to 0.09); P = .69] group. Both aerobic and combination groups had greater reductions in the composite Z-score compared with the resistance group (both P = .03), and there was no difference between the aerobic and combination groups (P = .96). Regarding the four individual CVD risk factors, only per cent body fat decreased in all three exercise groups at 1 year, but systolic blood pressure, LDL cholesterol, and fasting glucose did not decrease in any exercise groups, compared with the control group. CONCLUSIONS: In adults with overweight or obesity, aerobic exercise alone or combined resistance plus aerobic exercise, but not resistance exercise alone, improved composite CVD risk profile compared with the control.

Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Human DNA-dependent protein kinase catalytic subunit deficiency: a comprehensive review and update.

BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in PRKDC define the scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far. OBJECTIVE: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human. METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material. RESULTS: We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4+CD45RA+ T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y). CONCLUSION: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.

Evolving Spectrum of Adenosine Deaminase Deficiency: Assessing Genotype Pathogenicity Based on Expressed ADA Activity of 46 Variants.

BACKGROUND: Deficiency of adenosine deaminase 1 (ADA) has broad clinical and genetic heterogeneity. Screening techniques can identify asymptomatic infants whose phenotype and prognosis are indeterminate, and who may carry ADA variants of unknown significance. OBJECTIVE: To systematically assess the pathogenic potential of rare ADA missense variants, and to better define the relationship of red cell deoxyadenosine nucleotide (dAXP) content to phenotype. METHODS: We expressed 46 ADA missense variants in the ADA-deficient SØ3834 strain of E. coli and defined Genotype Categories (GC) ranked I - IV by increasing expressed ADA activity. We assessed relationships among GC rank, red cell dAXP, and phenotype in 58 reference patients with 50 different genotypes. We used our GC ranking system to benchmark AlphaMissense for predicting variant pathogenicity, and a minigene assay to identify an exonic splicing variant in ADA exon 9. RESULTS: The 46 missense variants expressed ∼0.001% to ∼70% of WT ADA activity (40% had <0.05% of WT ADA activity and 50% expressed >1%). Red cell dAXP ranged from undetectable to >75% of total adenine nucleotides and correlated well with phenotype. Both red cell dAXP and clinical severity were inversely related to "txADA" (total ADA activity expressed by both inherited variants). Our GC scoring system performed better than AlphaMissense in assessing variant pathogenicity, particularly for less deleterious variants. CONCLUSION: For ADA deficiency, pathogenicity is a continuum and conditional, depending on the total ADA activity contributed by both inherited variants as indicated by GC rank. However, in patients with indeterminate phenotype identified by screening, red cell dAXP measured at diagnosis may have greater prognostic value than GC rank .

Home and school pollutant exposure, respiratory outcomes, and influence of historical redlining.

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter [PM2.5], NO2) and respiratory outcomes (Composite Asthma Severity Index, lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N = 240) from 9 US cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of Composite Asthma Severity Index and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 parts per billion) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (P < .01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (P < .005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (P > .005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

The Convergence of Sonodynamic Therapy and Cuproptosis in the Dual-Responsive Biomimetic CytoNano for Precision Mitochondrial Intervention in Cancer Treatment.

The integration of sonodynamic therapy (SDT) with cuproptosis for targeted cancer treatment epitomizes a significant advancement in oncology. Herein, we present a dual-responsive therapeutic system, "CytoNano", which combines a cationic liposome infused with copper-nitride nanoparticles and oxygen-rich perfluorocarbon (Lip@Cu3N/PFC-O2), all enveloped in a biomimetic coating of neutrophil membrane and acid-responsive carboxymethylcellulose. CytoNano leverages the cellular mimicry of neutrophils and acid-responsive materials, enabling precise targeting of tumors and their acidic microenvironment. This strategic design facilitates the targeted release of Lip@Cu3N/PFC-O2 within the tumor, enhancing cancer cell uptake and mitochondrial localization. Consequently, it amplifies the therapeutic efficacy of both Cu3N-driven SDT and cuproptosis while preserving healthy tissues. Additionally, CytoNano's ultrasound responsiveness enhances intratumoral oxygenation, overcoming physiological barriers and initiating a combined sonodynamic-cuproptotic effect that induces multiple cell death pathways. Thus, we pioneer a biomimetic approach in precise sonodynamic cuproptosis, revolutionizing cancer therapy.

Programmed Remodeling of the Tumor Milieu to Enhance NK Cell Immunotherapy Combined with Chemotherapy for Pancreatic Cancer.

Natural killer (NK) cell-based adoptive immunotherapy has demonstrated encouraging therapeutic effects in clinical trials for hematological cancers. However, the effectiveness of treatment for solid tumors remains a challenge due to insufficient recruitment and infiltration of NK cells into tumor tissues. Herein, a programmed nanoremodeler (DAS@P/H/pp) is designed to remodel dense physical stromal barriers and for dysregulation of the chemokine of the tumor environment to enhance the recruitment and infiltration of NK cells in tumors. The DAS@P/H/pp is triggered by the acidic tumor environment, resulting in charge reversal and subsequent hyaluronidase (HAase) release. HAase effectively degrades the extracellular matrix, promoting the delivery of immunoregulatory molecules and chemotherapy drugs into deep tumor tissues. In mouse models of pancreatic cancer, this nanomediated strategy for the programmed remodeling of the tumor microenvironment significantly boosts the recruitment of NK92 cells and their tumor cell-killing capabilities under the supervision of multiplexed near-infrared-II fluorescence.