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Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.
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Neoplasias del Colon/patología , Células Mieloides/metabolismo , Análisis de la Célula Individual/métodos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Secuencia de Bases/genética , Linfocitos T CD8-positivos/inmunología , China , Neoplasias del Colon/terapia , Neoplasias Colorrectales/patología , Células Dendríticas/inmunología , Femenino , Humanos , Inmunoterapia , Macrófagos/inmunología , Masculino , Ratones , Persona de Mediana Edad , Análisis de Secuencia de ARN/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Galectin-4, a member of the galectin family of animal glycan-binding proteins (GBPs), is specifically expressed in gastrointestinal epithelial cells and is known to be able to bind microbes. However, its function in host-gut microbe interactions remains unknown. Here, we show that intracellular galectin-4 in intestinal epithelial cells (IECs) coats cytosolic Salmonella enterica serovar Worthington and induces the formation of bacterial chains and aggregates. Galectin-4 enchains bacteria during their growth by binding to the O-antigen of lipopolysaccharides. Furthermore, the binding of galectin-4 to bacterial surfaces restricts intracellular bacterial motility. Galectin-4 enhances caspase-1 activation and mature IL-18 production in infected IECs especially when autophagy is inhibited. Finally, orally administered S. enterica serovar Worthington, which is recognized by human galectin-4 but not mouse galectin-4, translocated from the intestines to mesenteric lymph nodes less effectively in human galectin-4-transgenic mice than in littermate controls. Our results suggest that galectin-4 plays an important role in host-gut microbe interactions and prevents the dissemination of pathogens. The results of the study revealed a novel mechanism of host-microbe interactions that involves the direct binding of cytosolic lectins to glycans on intracellular microbes.
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Galectina 4 , Inflamasomas , Animales , Ratones , Humanos , Inflamasomas/metabolismo , Galectina 4/metabolismo , Células Epiteliales/metabolismo , Bacterias , Antígenos O/metabolismoRESUMEN
Solid-state spin-photon interfaces that combine single-photon generation and long-lived spin coherence with scalable device integration-ideally under ambient conditions-hold great promise for the implementation of quantum networks and sensors. Despite rapid progress reported across several candidate systems, those possessing quantum coherent single spins at room temperature remain extremely rare. Here we report quantum coherent control under ambient conditions of a single-photon-emitting defect spin in a layered van der Waals material, namely, hexagonal boron nitride. We identify that the carbon-related defect has a spin-triplet electronic ground-state manifold. We demonstrate that the spin coherence is predominantly governed by coupling to only a few proximal nuclei and is prolonged by decoupling protocols. Our results serve to introduce a new platform to realize a room-temperature spin qubit coupled to a multiqubit quantum register or quantum sensor with nanoscale sample proximity.
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Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCFFBXO5-APC/C-GMNN and CUL4DTL-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.
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Replicación del ADN , Ubiquitina-Proteína Ligasas , Azepinas/metabolismo , Complejo del Señalosoma COP9/antagonistas & inhibidores , Complejo del Señalosoma COP9/genética , Complejo del Señalosoma COP9/metabolismo , Supervivencia Celular , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Imidazoles/metabolismo , Proteína NEDD8/metabolismo , Pirazoles/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Glioma is a type of tumor that starts in the glial cells of the brain or spine. Since the 1800s, when the disease was first named, its survival rates have always been unsatisfactory. Despite great advances in molecular biology and traditional treatment methods, many questions regarding cancer occurrence and the underlying mechanism remain to be answered. In this study, we assessed the protein structural features of 20 oncogenes and 20 anti-oncogenes via protein structure and dynamic analysis methods and 3D structural and systematic analyses of the structure-function relationships of proteins. All of these results directly indicate that unfavorable group proteins show more complex structures than favorable group proteins. As the tumor cell microenvironment changes, the balance of oncogene-related and anti-oncogene-related proteins is disrupted, and most of the structures of the two groups of proteins will be disrupted. However, more unfavorable group proteins will maintain and refold to achieve their correct shape faster and perform their functions more quickly than favorable group proteins, and the former thus support cancer development. We hope that these analyses will help promote mechanistic research and the development of new treatments for glioma.
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Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/metabolismo , Glioma/patología , Oncogenes , Microambiente TumoralRESUMEN
This study investigated the ERK pathway of the peripheral nervous system and discovered a gender-specific pattern of ERK activation in the dorsal root ganglion of an acid-induced chronic widespread muscular pain model. We employed a twice acid-induced chronic musculoskeletal pain model in rats to evaluate mechanical pain behavior in both male and female groups. We further conducted protein analysis of dissected dorsal root ganglions from both genders. Both male and female rats exhibited a similar pain behavior trend, with females demonstrating a lower pain threshold. Protein analysis of the dorsal root ganglion (DRG) showed a significant increase in phosphorylated ERK after the second acid injection in all groups. However, phosphorylation of ERK was observed in the dorsal root ganglion, with higher levels in the male ipsilateral group compared to the female group. Moreover, there was a no difference between the left and right sides in males, whereas the significant difference was observed in females. In conclusions, the administration of acid injections induced painful behavior in rats, and concurrent with this, a significant upregulation of pERK was observed in the dorsal root ganglia, with a greater magnitude of increase in males than females, and in the contralateral side compared to the ipsilateral side. Our findings shed light on the peripheral mechanisms underlying chronic pain disorders and offer potential avenues for therapeutic intervention.
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Quinasas MAP Reguladas por Señal Extracelular , Fibromialgia , Ganglios Espinales , Ratas Sprague-Dawley , Caracteres Sexuales , Animales , Masculino , Femenino , Fibromialgia/metabolismo , Ganglios Espinales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Umbral del Dolor , Modelos Animales de Enfermedad , Dolor/metabolismo , Dolor/fisiopatologíaRESUMEN
KRAS gene mutations are common in pancreatic ductal adenocarcinoma (PDAC), but targeting mutant KRAS is still challenging. Here, an endoribonuclease-prepared small interfering RNA (esiRNA) library was used to screen new kinases that play critical roles in PDAC driven by KRAS gene mutations, and serine/threonine kinase 31 (STK31) was identified and characterized as a potential therapeutic target for KRAS-mutant PDAC. Our results showed that STK31 was upregulated in KRAS-mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRASG12D mutation. Inhibition of STK31 in KRAS-mutant cell lines significantly reduced PDAC cell growth in vitro and hindered tumor growth in vivo. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. A pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c-Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. Through RNA sequencing, we found that the cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Taken together, our results indicate that STK31, which is the downstream target of the KRAS/MAPK/ERK/c-Jun signaling pathway in KRAS-mutant PDAC, promotes PDAC cell growth by modulating the expression of the cell cycle regulators CCNB1 and CDC25C.
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Visualization of the mitochondrial state is crucial for tracking cell life processes and diagnosing disease, while fluorescent probes that can accurately assess mitochondrial status are currently scarce. Herein, a fluorescent probe named "SYN" was designed and prepared, which can target mitochondria via the mitochondrial membrane potential. Upon pathology or external stimulation, SYN can be released from the mitochondria and accumulate in the nucleolus to monitor the status of mitochondria. During this process, the brightness of the nucleolus can then serve as an indicator of mitochondrial damage. SYN has demonstrated excellent photostability in live cells as well as an extremely inert fluorescence response to bioactive molecules and the physiological pH environment of live cells. Spectroscopic titration and molecular docking studies have revealed that SYN can be lit up in nucleoli due to the high viscosity of the nucleus and the strong electrostatic interaction with the phosphate backbone of RNA. This probe is expected to be an exceptional tool based on its excellent imaging properties for tracking mitochondrial state in live cells.
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Nucléolo Celular , Colorantes Fluorescentes , Mitocondrias , Mitocondrias/metabolismo , Mitocondrias/química , Humanos , Colorantes Fluorescentes/química , Nucléolo Celular/metabolismo , Células HeLa , Simulación del Acoplamiento Molecular , Imagen Óptica , Potencial de la Membrana MitocondrialRESUMEN
Detecting proteins in ultralow concentrations in complex media is important for many applications but often relies on complicated techniques. Herein, a single-molecule protein analyzer with the potential for high-throughput applications is reported. Gold-coated magnetic nanoparticles with DNA-labeled antibodies were used for target recognition and separation. The immunocomplex was loaded into microdroplets generated with centrifugation. Immuno-PCR amplification of the DNA enabled the quantification of proteins at the level of single molecules. As an example, ultrasensitive detection of α-synuclein, a biomarker for neurodegenerative diseases, is achieved. The limit of detection was determined to be â¼50 aM in buffer and â¼170 aM in serum. The method exhibited high specificity and could be used to analyze post-translational modifications such as protein phosphorylation. This study will inspire wider studies on single-molecule protein detection, especially in disease diagnostics, biomarker discovery, and drug development.
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Nanopartículas de Magnetita , Nanopartículas del Metal , Pruebas Inmunológicas , ADN , Magnetismo , Biomarcadores/análisis , OroRESUMEN
The efficacy of electron transport layers (ETLs) is pivotal for optimizing the device performance of perovskite photovoltaic applications. However, colloidal dispersions of SnO2 are prone to aggregation and possess structural defects, such as terminal-hydroxyls (OHT) and oxygen vacancies (VOs), which can degrade the quality of ETLs, impede charge extraction and transport, and affect the nucleation and growth processes of the perovskite layer. In this study, the Sb(OH)4 - ions hydrolyzed from SbCl3 in colloidal dispersion can bind to defect sites and effectively stabilize the SnO2 nanocrystals are demonstrated. Upon oxidative annealing, a Sb2O5@SnO2 composite film is formed, in which the Sb2O5 not only mitigates the aforementioned defects but also broadens the energy range of unoccupied states through its dispersed conduction band. The increased electron affinity (EA) facilitates more efficient capture of photoexcited electrons from the perovskite layer, thus augmenting electron extraction and minimizing electron-hole recombination. As a result, a significant improvement in power conversion efficiency (PCE) from 22.60% to 24.54% is achieved, with an open circuit voltage (VOC) of up to 1.195 V, along with excellent stability of unsealed devices under various conditions. This study provides valuable insights for the understanding and design of ETLs in perovskite photovoltaic applications.
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Arabidopsis RESISTANCE TO POWDERY MILDEW 8.1 (RPW8.1) is an important tool for engineering broad-spectrum disease resistance against multiple pathogens. Ectopic expression of RPW8.1 leads to enhanced disease resistance with cell death at leaves and compromised plant growth, implying a regulatory mechanism balancing RPW8.1-mediated resistance and growth. Here, we show that RPW8.1 constitutively enhances the expression of transcription factor WRKY51 and activates salicylic acid and ethylene signalling pathways; WRKY51 in turn suppresses RPW8.1 expression, forming a feedback regulation loop. RPW8.1 and WRKY51 are both induced by pathogen infection and pathogen-/microbe-associated molecular patterns. In ectopic expression of RPW8.1 background (R1Y4), overexpression of WRKY51 not only rescues the growth suppression and cell death caused by RPW8.1, but also suppresses RPW8.1-mediated broad-spectrum disease resistance and pattern-triggered immunity. Mechanistically, WRKY51 directly binds to and represses RPW8.1 promoter, thus limiting the expression amplitude of RPW8.1. Moreover, WRKY6, WRKY28 and WRKY41 play a role redundant to WRKY51 in the suppression of RPW8.1 expression and are constitutively upregulated in R1Y4 plants with WRKY51 being knocked out (wrky51 R1Y4) plants. Notably, WRKY51 has no significant effects on disease resistance or plant growth in wild type without RPW8.1, indicating a specific role in RPW8.1-mediated disease resistance. Altogether, our results reveal a regulatory circuit controlling the accumulation of RPW8.1 to an appropriate level to precisely balance growth and disease resistance during pathogen invasion.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Resistencia a la Enfermedad/genética , Retroalimentación , Arabidopsis/metabolismo , Muerte Celular , Enfermedades de las Plantas/genética , Regulación de la Expresión Génica de las Plantas/genéticaRESUMEN
Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.
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BACKGROUND: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. METHODS: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. RESULTS: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. CONCLUSIONS: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.
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Péptido Relacionado con Gen de Calcitonina , Piperidinas , Piridinas , Pirroles , Receptores de Péptido Relacionado con el Gen de Calcitonina , Compuestos de Espiro , Humanos , Ratas , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Hiperalgesia/tratamiento farmacológicoRESUMEN
BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.
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Protocolos de Quimioterapia Combinada Antineoplásica , Factor de Transcripción Ikaros , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Factor de Transcripción Ikaros/genética , Masculino , Femenino , Pronóstico , Niño , Preescolar , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Lactante , Adolescente , Resultado del Tratamiento , Eliminación de Gen , China/epidemiologíaRESUMEN
Cytosolic lipopolysaccharides (LPSs) bind directly to caspase-4/5/11 through their lipid A moiety, inducing inflammatory caspase oligomerization and activation, which is identified as the noncanonical inflammasome pathway. Galectins, ß-galactoside-binding proteins, bind to various gram-negative bacterial LPS, which display ß-galactoside-containing polysaccharide chains. Galectins are mainly present intracellularly, but their interactions with cytosolic microbial glycans have not been investigated. We report that in cell-free systems, galectin-3 augments the LPS-induced assembly of caspase-4/11 oligomers, leading to increased caspase-4/11 activation. Its carboxyl-terminal carbohydrate-recognition domain is essential for this effect, and its N-terminal domain, which contributes to the self-association property of the protein, is also critical, suggesting that this promoting effect is dependent on the functional multivalency of galectin-3. Moreover, galectin-3 enhances intracellular LPS-induced caspase-4/11 oligomerization and activation, as well as gasdermin D cleavage in human embryonic kidney (HEK) 293T cells, and it additionally promotes interleukin-1ß production and pyroptotic death in macrophages. Galectin-3 also promotes caspase-11 activation and gasdermin D cleavage in macrophages treated with outer membrane vesicles, which are known to be taken up by cells and release LPSs into the cytosol. Coimmunoprecipitation confirmed that galectin-3 associates with caspase-11 after intracellular delivery of LPSs. Immunofluorescence staining revealed colocalization of LPSs, galectin-3, and caspase-11 independent of host N-glycans. Thus, we conclude that galectin-3 amplifies caspase-4/11 oligomerization and activation through LPS glycan binding, resulting in more intense pyroptosis-a critical mechanism of host resistance against bacterial infection that may provide opportunities for new therapeutic interventions.
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Caspasas/metabolismo , Galectina 3/metabolismo , Inflamasomas/inmunología , Inflamación/inmunología , Lipopolisacáridos/metabolismo , Macrófagos/inmunología , Animales , Citosol/metabolismo , Galectina 3/genética , Inflamasomas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , PiroptosisRESUMEN
Appetite hormone dysregulation may play a role in the pathomechanisms of bipolar disorder and chronic irritability. However, its association with executive dysfunction in adolescents with bipolar disorder and those with disruptive mood dysregulation disorder (DMDD) remains unclear. We included 20 adolescents with bipolar disorder, 20 adolescents with DMDD, and 47 healthy controls. Fasting serum levels of appetite hormones, including leptin, ghrelin, insulin, and adiponectin were examined. All participants completed the Wisconsin Card Sorting Test. Generalized linear models with adjustments for age, sex, body mass index, and clinical symptoms revealed that patients with DMDD had elevated fasting log-transformed insulin levels (p = .023) compared to the control group. Adolescents with DMDD performed worse in terms of the number of tries required to complete tasks associated with the first category (p = .035), and adolescents with bipolar disorder performed worse in terms of the number of categories completed (p = .035). A positive correlation was observed between log-transformed insulin levels and the number of tries required for the first category (ß = 1.847, p = .032). Adolescents with DMDD, but not those with bipolar disorder, were more likely to exhibit appetite hormone dysregulation compared to healthy controls. Increased insulin levels were also related to executive dysfunction in these patients. Prospective studies should elucidate the temporal association between appetite hormone dysregulation, executive dysfunction, and emotional dysregulation.
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BACKGROUND: The risks of sexually transmitted infections (STIs) and teenage pregnancy in the offspring of parents with schizophrenia remain unknown. METHODS: From the Taiwan National Health Insurance Research Database, 5,850 individuals born between 1980 and 1999 having any parent with schizophrenia and 58,500 age-, sex-, income- and residence-matched controls without parents with severe mental disorders were enrolled in 1996 or on their birthdate and followed up to the end of 2011. Those who contracted any STI or became pregnant in adolescence during the follow-up period were identified. RESULTS: Cox regression analyses demonstrated that offspring of parents with schizophrenia (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 1.02-1.44), especially daughters (HR: 1.30, 95% CI: 1.06-1.58), were more likely to contract any STI later in life than the control comparisons. In addition, daughters of parents with schizophrenia had an elevated risk of being pregnant in their adolescence (HR: 1.47, 95% CI: 1.29-1.67) compared with those having no parents with severe mental disorders. DISCUSSION: The positive relationship between parental schizophrenia and offspring STIs and teenage pregnancy necessitates clinicians and public health officers to closely monitor the sexual health in the offspring of parents with schizophrenia so that optimal and prompt preventive measures can be taken in the at-risk group.
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INTRODUCTION: Family engagement in care has been advocated to promote recovery for patients with mental health conditions. Attitudes of mental health nurses toward the importance of families influence the way they partner with families in mental healthcare. However, little is known about how mental health nurses engage with families and quality of family-centered care (FCC) perceived by patients and caregivers. The study aimed to examine the mediating effect of family nursing practice on the association between mental health nurses' attitudes toward integrating families into care and quality of FCC perceived by patients with schizophrenia and caregivers. DESIGN: A cross-sectional study was conducted. METHODS: A convenience sample of 143 dyads of patients with schizophrenia and their caregivers and 109 mental health nurses were recruited from inpatient wards at two psychiatric hospitals in Taiwan. Demographic and clinical questionnaires, Families' Importance in Nursing Care-Nurses' Attitudes scale, Family Nursing Practice Scale, and Measure of Process of Care for Adults were used to collect data. Data were analyzed using descriptive statistics, independent-sample t-tests, one-way analysis of variance, Pearson correlation coefficients, paired-sample t-tests, and intraclass correlation coefficient (ICC). Mediation analyses were performed using Hayes' PROCESS macro in SPSS (Model 4) with bootstrapping. RESULTS: Mental health nurses exhibited supportive attitudes toward integrating families into care (Mean = 98.96) and greater perceptions of family nursing practice (Mean = 2.44). The concordances between patients and caregivers on perceived quality of family-centered care were significant (ICC = 0.63-0.77). Attitudes of mental health nurses toward integrating families into care had both the total and direct effects on all domains of quality of FCC perceived by patients and caregivers, respectively. The indirect effects of mental health nurses' attitudes toward integrating families into care on aspects of quality of FCC through family nursing practice were significant for patients (95% bias-corrected bootstrap CI of 0.015-0.053) and caregivers (95% bias-corrected bootstrap CI of 0.004-0.041). The magnitude of the indirect effects was medium to large for patients (ES = 0.209-0.257) and caregivers (ES = 0.148-0.221). CONCLUSION: Family nursing practice partially mediated the association between mental health nurses' attitudes toward integrating families into care and aspects of quality of FCC from perspectives of patients and caregivers. CLINICAL RELEVANCE: Interventions tailoring mental health nurses' practice skills and reciprocity with families have the potential to enhance supportive attitudes of mental health nurses toward working with families and further improve perceived quality of FCC in patient-caregiver dyads in mental healthcare practice.
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BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.