Green Light from Red-Emitting Nanocrystals: Broadband, Low-Threshold Lasing from Colloidal Quantum Shells in Optical Nanocavities.

Spherical semiconductor nanoplatelets, known as quantum shells (QSs), have captured significant interest for their strong suppression of Auger recombination, which leads to long multiexciton lifetimes and wide optical gain bandwidth. Yet, the realization of benefits associated with the multiexciton lasing regime using a suitably designed photonic cavity remains elusive. Here, we demonstrate broadly tunable lasing from close-packed films of CdS/CdSe/CdS QSs deposited over nanopillar arrays on Si substrates. Wide spectral tuning of the stimulated emission in QSs with a fixed bandgap value was achieved by engaging single exciton (λX ∼ 634 nm), biexciton (λBX ∼ 627 nm), and multiple exciton (λMX ∼ 615-565 nm) transitions. The ensemble-averaged gain threshold of ∼ 2.6 electron-hole pairs per QS particle and the low photonic cavity fluence threshold of ∼4 µJ/cm2 were attributed to Auger suppression. The tuning of the lasing emission closely aligns with our model predictions achieved by varying the array period while preserving mode confinement and quality (Q) factors. These results mark a notable step toward the development of colloidal nanocrystal lasers.

Contribution of monocyte and macrophage extracellular traps to neutrophilic airway inflammation in severe asthma.

BACKGROUND: Increased blood/sputum neutrophil counts are related to poor clinical outcomes of severe asthma (SA), where we hypothesized that classical monocytes (CMs)/CM-derived macrophages (Mφ) are involved. We aimed to elucidate the mechanisms of how CMs/Mφ induce the activation of neutrophils/innate lymphoid cells (ILCs) in SA. METHODS: Serum levels of monocyte chemoattractant protein-1 (MCP-1) and soluble suppression of tumorigenicity 2 (sST2) were measured from 39 patients with SA and 98 those with nonsevere asthma (NSA). CMs/Mφ were isolated from patients with SA (n = 19) and those with NSA (n = 18) and treated with LPS/interferon-gamma. Monocyte/M1Mφ extracellular traps (MoETs/M1ETs) were evaluated by western blotting, immunofluorescence, and PicoGreen assay. The effects of MoETs/M1ETs on neutrophils, airway epithelial cells (AECs), ILC1, and ILC3 were assessed in vitro and in vivo. RESULTS: The SA group had significantly higher CM counts with increased migration as well as higher levels of serum MCP-1/sST2 than the NSA group. Moreover, the SA group had significantly greater production of MoETs/M1ETs (from CMs/M1Mφ) than the NSA group. The levels of MoETs/M1ETs were positively correlated with blood neutrophils and serum levels of MCP-1/sST2, but negatively correlated with FEV1%. In vitro/in vivo studies demonstrated that MoETs/M1ETs could activate AECs, neutrophils, ILC1, and ILC3 by increased migration as well as proinflammatory cytokine production. CONCLUSIONS: CM/Mφ-derived MoETs/M1ETs could contribute to asthma severity by enhancing neutrophilic airway inflammation in SA, where modulating CMs/Mφ may be a potential therapeutic option.

Phase-specific differential regulation of mechanical allodynia in a murine model of neuropathic pain by progesterone.

Progesterone has been shown to have neuroprotective capabilities against a wide range of nervous system injuries, however there are negative clinical studies that have failed to demonstrate positive effects of progesterone therapy. Specifically, we looked into whether progesterone receptors or its metabolizing enzymes, cytochrome P450c17 and 5α-reductase, are involved in the effects of progesterone on neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve in mice. Intrathecal progesterone administration during the induction phase of chronic pain enhanced mechanical allodynia development and spinal glial fibrillary acidic protein (GFAP) expression, and this enhancement was inhibited by administration of ketoconazole, a P450c17 inhibitor, but not finasteride, a 5α-reductase inhibitor. Furthermore, phospho-serine levels of P450c17 in the spinal cord were elevated on day 1 after CCI operation, but not on day 17. In contrast, intrathecal progesterone administration during the maintenance phase of chronic pain decreased the acquired pain and elevated GFAP expression; this inhibition was restored by finasteride administration, but not by ketoconazole. The modification of mechanical allodynia brought on by progesterone in CCI mice was unaffected by the administration of mifepristone, a progesterone receptor antagonist. Collectively, these findings imply that progesterone suppresses spinal astrocyte activation via 5α-reductase activity during the maintenance phase of chronic pain and has an analgesic impact on the mechanical allodynia associated with the growing neuropathy. Progesterone, however, stimulates spinal astrocytes during the induction stage of peripheral neuropathy and boosts the allodynic impact caused by CCI through early spinal P450c17 activation.

Antinociceptive effect of intermittent fasting via the orexin pathway on formalin-induced acute pain in mice.

It has been suggested that stress responses induced by fasting have analgesic effects on nociception by elevating the levels of stress-related hormones, while there is limited understanding of pain control mechanisms. Here, we investigated whether acute or intermittent fasting alleviates formalin-induced pain in mice and whether spinal orexin A (OXA) plays a role in this process. 6, 12, or 24 h acute fasting (AF) and 12 or 24 h intermittent fasting (IF) decreased the second phase of pain after intraplantar formalin administration. There was no difference in walking time in the rota-rod test and distance traveld in the open field test in all groups. Plasma corticosterone level and immobility time in the forced swim test were increased after 12 h AF, but not after 12 h IF. 12 h AF and IF increased not only the activation of OXA neurons in the lateral hypothalamus but also the expression of OXA in the lateral hypothalamus and spinal cord. Blockade of spinal orexin 1 receptor with SB334867 restored formalin-induced pain and spinal c-Fos immunoreactivity that were decreased after 12 h IF. These results suggest that 12 h IF produces antinociceptive effects on formalin-induced pain not by corticosterone elevation but by OXA-mediated pathway.

NAG-1/GDF-15 Transgenic Female Mouse Shows Delayed Peak Period of the Second Phase Nociception in Formalin-induced Inflammatory Pain.

Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), also known as growth differentiation factor-15 (GDF-15), is associated with cancer, diabetes, and inflammation, while there is limited understanding of the role of NAG-1 in nociception. Here, we examined the nociceptive behaviors of NAG-1 transgenic (TG) mice and wild-type (WT) littermates. Mechanical sensitivity was evaluated by using the von Frey filament test, and thermal sensitivity was assessed by the hot-plate, Hargreaves, and acetone tests. c-Fos, glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule-1 (Iba-1) immunoreactivity was examined in the spinal cord following observation of the formalin-induced nociceptive behaviors. There was no difference in mechanical or thermal sensitivity for NAG-1 TG and WT mice. Intraplantar formalin injection induced nociceptive behaviors in both male and female NAG-1 TG and WT mice. The peak period in the second phase was delayed in NAG-1 TG female mice compared with that of WT female mice, while there was no difference in the cumulative time of nociceptive behaviors between the two groups of mice. Formalin increased spinal c-Fos immunoreactivity in both TG and WT female mice. Neither GFAP nor Iba-1 immunoreactivity was increased in the spinal cord of TG and WT female mice. These findings indicate that NAG-1 TG mice have comparable baseline sensitivity to mechanical and thermal stimulation as WT mice and that NAG-1 in female mice may have an inhibitory effect on the second phase of inflammatory pain. Therefore, it could be a novel target to inhibit central nervous system response in pain.

Topological Microlaser with a Non-Hermitian Topological Bulk.

Bulk-edge correspondence, with quantized bulk topology leading to protected edge states, is a hallmark of topological states of matter and has been experimentally observed in electronic, atomic, photonic, and many other systems. While bulk-edge correspondence has been extensively studied in Hermitian systems, a non-Hermitian bulk could drastically modify the Hermitian topological band theory due to the interplay between non-Hermiticity and topology, and its effect on bulk-edge correspondence is still an ongoing pursuit. Importantly, including non-Hermicity can significantly expand the horizon of topological states of matter and lead to a plethora of unique properties and device applications, an example of which is a topological laser. However, the bulk topology, and thereby the bulk-edge correspondence, in existing topological edge-mode lasers is not well defined. Here, we propose and experimentally probe topological edge-mode lasing with a well-defined non-Hermitian bulk topology in a one-dimensional (1D) array of coupled ring resonators. By modeling the Hamiltonian with an additional degree of freedom (referred to as synthetic dimension), our 1D structure is equivalent to a 2D non-Hermitian Chern insulator with precise mapping. Our Letter may open a new pathway for probing non-Hermitian topological effects and exploring non-Hermitian topological device applications.

Tissue Inhibitor of Metalloproteinase-1 Enhances Eosinophilic Airway Inflammation in Severe Asthma.

PURPOSE: Severe asthma (SA) is characterized by persistent airway inflammation and remodeling, followed by lung function decline. The present study aimed to evaluate the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the pathogenesis of SA. METHODS: We enrolled 250 adult asthmatics (54 with SA and 196 with non-SA) and 140 healthy controls (HCs). Serum TIMP-1 levels were determined by enzyme-linked immunosorbent assay. The release of TIMP-1 from airway epithelial cells (AECs) in response to stimuli as well as the effects of TIMP-1 on the activations of eosinophils and macrophages were evaluated in vitro and in vivo. RESULTS: Significantly higher levels of serum TIMP-1 were noted in asthmatics than in HCs, in the SA group than in non-SA group, and in the type 2 SA group than in non-type 2 SA group (P < 0.01 for all). A negative correlation between serum TIMP-1 and FEV1% values (r = -0.400, P = 0.003) was noted in the SA group. In vitro study demonstrated that TIMP-1 was released from AECs in response to poly I:C, IL-13, eosinophil extracellular traps (EETs) and in coculture with eosinophils. TIMP-1-stimulated mice showed eosinophilic airway inflammation, which was not completely suppressed by steroid treatment. In vitro and in vivo functional studies showed that TIMP-1 directly activated eosinophils and macrophages, and induced the release of EETs and macrophages to polarize toward M2 subset, which was suppressed by anti-TIMP-1 antibody. CONCLUSIONS: These findings suggest that TIMP-1 enhances eosinophilic airway inflammation and that serum TIMP-1 may be a potential biomarker and/or therapeutic target for type 2 SA.

Social engagement and subjective health among older adults in South Korea: Evidence from the Korean Longitudinal Study of Aging (2006-2018).

Background: Social engagement serves as the foundation for social connections by providing a sense of belonging, social identity, and fulfillment. Previous studies have mainly focused on the one-way relationship between social engagement and subjective health among older individuals, and little attention has been paid to their mutual relationship. Therefore, this study aimed to examine the mutual association relationship between social engagement and their subjective health in older Koreans. Methods: Seven waves of data samples (aged ≥60 years) from 2006 to 2018 from the Korean Longitudinal Study of Aging (KLoSA) was used in this study. Descriptive analysis, chi-squared tests, 2-year lagged Generalized estimating equation (GEE) model, and cross-lagged panel model were performed to investigate the mutual association between social engagement and subjective health among six survey periods. Results: Results of the GEE model revealed when controlling for other variables, older Koreans who reported good subjective health only had a higher OR (1.678 vs. 1.650, p < 0.001) of participating in social engagement than those who had bad subjective health in 2006-2008 period; the occurrence rate of more social engagement was significantly higher among older adults with good subjective health than among those with bad subjective health (five out six survey periods). Cross-lagged analysis showed similar results that coefficients of social engagement on subjective were relatively larger in three survey periods; coefficients of subjective health on social engagement were relatively larger in the other three survey periods. The impact of social engagement on subjective health might be greater than that of subjective health on social engagement. Conclusion: All-around participation and engagement of older people in society have become a consensus among the international community. In view of the single social engagement activities and less relevant participation channels in Korea, government departments should consider not only regional but also local characteristics to create more social participation opportunities for older individuals.

Characterization of human induced pluripotent stem cells line (PNUSCRi004-A) from a Parkinson's disease patient carrying L483P, A495P and V499V mutations.

The hiPSC line was generated from peripheral blood mononuclear cells (PBMCs) collected from a female patient with young onset Parkinson's disease (PD), carrying on heterozygous c.1448 T > C (L483P), c1483 G > C (A495P) and c.1497 G > C (V499V) mutations in the GBA gene. The PBMCs was reprogrammed into an induced pluripotent stem cell (iPSC) line (GBA PD8 or PNUSCRi004-A hiPSCs) using non-integrative Sendai virus. The cell line, PNUSCRi004-A displayed a normal karyotype and expression of pluripotency markers capable of producing derivatives of three germ layers (Ectoderm, Endoderm and Mesoderm).

Metal-Halide Perovskite Lasers: Cavity Formation and Emission Characteristics.

Hybrid metal-halide perovskites (MHPs) have shown remarkable optoelectronic properties as well as facile and cost-effective processability. With the success of MHP solar cells and light-emitting diodes, MHPs have also exhibited great potential as gain media for on-chip lasers. However, to date, stable operation of optically pumped MHP lasers and electrically driven MHP lasers-an essential requirement for MHP laser's insertion into chip-scale photonic integrated circuits-is not yet demonstrated. The main obstacles include the instability of MHPs in the atmosphere, rudimentary MHP laser cavity patterning methods, and insufficient understanding of emission mechanisms in MHP materials and cavities. This review aims to provide a detailed overview of different strategies to improve the intrinsic properties of MHPs in the atmosphere and to establish an optimal MHP cavity patterning method. In addition, this review discusses different emission mechanisms in MHP materials and cavities and how to distinguish them.

Health-related quality of life using WHODAS 2.0 and associated factors 1 year after stroke in Korea: a multi-centre and cross-sectional study.

BACKGROUND: Little is known about the self-perceived level of disability of stroke survivors in the community. We aimed to characterise Health-related quality of life (HRQoL) 1 year after stroke and investigate how sociodemographic and stroke-related factors and medical adherence explain the self-perceived level of disability in a Korean stroke population. METHODS: This was a multicentre cross-sectional study. A total of 382 ischaemic stroke survivors at 1 year after onset from 11 university hospitals underwent a one-session assessment, including socioeconomic variables, the modified Rankin Scale (mRS), various neurological sequelae, the Morisky, Green and Levin-Medication Adherence Questionnaire (MGL), and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) 36-items. The relationship between disability and different variables was analysed using ordinal logistic regression. RESULTS: The prevalence of disability based on global WHODAS 2.0 was 62.6% (mild, 41.6%; moderate, 16.0%; severe, 5.0%). The prevalence of severe disability was higher in participation in society (16.8%) and getting around (11.8%) than in other domains. Low MGL- motivation was the only factor determining a significant association between all six domains of disability after adjustment. Different predictors for specific domains were age, mRS, dysarthria, trouble seeing, cognition problems, and MGL-motivation for understanding and communicating; age, recurrent stroke, mRS, hemiplegia, facial palsy, general weakness, and MGL-motivation for getting around; age, education, mRS, hemiplegia, and MGL-motivation for self-care; education, recurrent stroke, hemiplegia, dysarthria, and MGL-motivation for getting along with people; age, education, income, mRS, hemiplegia, dysarthria, MGL-knowledge, and MGL-motivation for life activities; living without a spouse, mRS, hemiplegia, dysarthria, trouble seeing, cognition problems, general weakness, and MGL-motivation for participation in society. CONCLUSIONS: Self-perceived disability according to the WHODAS 2.0 at 1 year after stroke was highly prevalent. Each disability domain showed a different prevalence and associated factors. Interventions promoting medical adherence to motivation seemed to help achieve high HRQoL in all domains.

Generation of Parkinson's disease patient-derived human induced pluripotent stem cells line (PNUSCRi001-A) carrying a N227S mutation in GBA gene.

The hiPSC line was generated from peripheral blood mononuclear cells (PBMCs) collected by a male patient with young onset Parkinson's disease, carrying on heterozygous c.680 A > G (N227S) mutation in the GBA gene. The PBMCs was reprogrammed into an induced pluripotent stem cell (iPSC) line (PNUSCRi001-A hiPSCs) using non-integrative sendai virus. The hiPSC line, PNUSCRi001-A displayed a normal karyotype and the Expression of pluripotency markers that is capable of producing derivatives of three germ layers (Ectoderm, Endoderm and Mesoderm).

Human induced pluripotent stem cells line (PNUSCRi002-A) from a patient with Parkinson's disease carrying a R159W mutation in the GBA gene.

Mutation in the glucocerebrosidase encoding gene 1 (GBA) is one of the most frequent causes of Parkinson's disease (PD). Herein, we obtained peripheral blood mononuclear cells (PBMCs) from a patient with PD with a heterozygous c.475C > T (p.R159W) mutation in the GBA gene, and generated an induced pluripotent stem cell (iPSC) line (GBA PD9 or PNUSCRi002-A hiPSCs) using a non-integrative Sendai virus. The iPSC line expressed pluripotency markers (OCT4, NANOG, SSEA-4, TRA-1-60) and displayed differentiation properties in the three germ layers (ectoderm, endoderm, and mesoderm). Additionally, the patient had a normal karyotype.

Detection of serum IgG autoantibodies to FcεRIα by ELISA in patients with chronic spontaneous urticaria.

BACKGROUND: Mast cells are a key effector cell in the pathogenesis of chronic spontaneous urticaria (CSU) and activated by circulating FcεRI-specific IgG as well as IgE. This study evaluated the prevalence of circulating autoantibodies to FcεRIα in the sera of CSU patients. METHODS: Eighty-eight patients with CSU and 76 healthy controls (HCs) were enrolled. To detect circulating autoantibodies (IgG/IgA/IgM) to FcεRIα, ELISA was done using YH35324 (as a solid phase antigen), and its binding specificity was confirmed by the ELISA inhibition test. The antibody levels were presented by the ratio of YH35324-preincubated to mock-preincubated absorbance values. Clinical and autoimmune parameters, including atopy, urticaria activity score (UAS), serum total/free IgE levels, serum antinuclear antibody (ANA) and autologous serum skin test (ASST) results, were assessed. The autoimmune group was defined if CSU patients had positive results to ASST and/or ANA. RESULTS: The ratio of serum IgG to FcεRIα was significantly lower in CSU patients than in HCs (P<0.05), while no differences were noted in serum levels of IgG to recombinant FcεRIα or IgA/IgM autoantibodies. The autoimmune CSU group had significantly lower ratios of IgG/IgA (not IgM) autoantibodies to FcεRIα than the nonautoimmune CSU group (P<0.05 for each). No significant associations were found between sex, age, atopy, urticaria duration, UAS, or serum total/free IgE levels according to the presence of IgG/IgA/IgM antibodies. CONCLUSIONS: This study confirmed the presence of IgG to FcεRIα in the sera of CSU patients, especially those with the autoimmune phenotype.

Data Collection Framework for Context-Aware Virtual Reality Application Development in Unity: Case of Avatar Embodiment.

Virtual Reality (VR) has been adopted as a leading technology for the metaverse, yet most previous VR systems provide one-size-fits-all experiences to users. Context-awareness in VR enables personalized experiences in the metaverse, such as improved embodiment and deeper integration of the real world and virtual worlds. Personalization requires context data from diverse sources. We proposed a reusable and extensible context data collection framework, ManySense VR, which unifies data collection from diverse sources for VR applications. ManySense VR was implemented in Unity based on extensible context data managers collecting data from data sources such as an eye tracker, electroencephalogram, pulse, respiration, galvanic skin response, facial tracker, and Open Weather Map. We used ManySense VR to build a context-aware embodiment VR scene where the user's avatar is synchronized with their bodily actions. The performance evaluation of ManySense VR showed good performance in processor usage, frame rate, and memory footprint. Additionally, we conducted a qualitative formative evaluation by interviewing five developers (two males and three females; mean age: 22) after they used and extended ManySense VR. The participants expressed advantages (e.g., ease-of-use, learnability, familiarity, quickness, and extensibility), disadvantages (e.g., inconvenient/error-prone data query method and lack of diversity in callback methods), future application ideas, and improvement suggestions that indicate potential and can guide future development. In conclusion, ManySense VR is an efficient tool for researchers and developers to easily integrate context data into their Unity-based VR applications for the metaverse.

Bile Acid Conjugation on Solid Nanoparticles Enhances ASBT-Mediated Endocytosis and Chylomicron Pathway but Weakens the Transcytosis by Inducing Transport Flow in a Cellular Negative Feedback Loop.

Bile acid-modified nanoparticles provide a convenient strategy to improve oral bioavailability of poorly permeable drugs by exploiting specific interactions with bile acid transporters. However, the underlying mechanisms are unknown, especially considering the different absorption sites of free bile acids (ileum) and digested fat molecules from bile acid-emulsified fat droplets (duodenum). Here, glycocholic acid (GCA)-conjugated polystyrene nanoparticles (GCPNs) are synthesized and their transport in Caco-2 cell models is studied. GCA conjugation enhances the uptake by interactions with apical sodium-dependent bile acid transporter (ASBT). A new pathway correlated with both ASBT and chylomicron pathways is identified. Meanwhile, the higher uptake of GCPNs does not lead to higher transcytosis to the same degree compared with unmodified nanoparticles (CPNs). The pharmacological and genomics study confirm that GCA conjugation changes the endocytosis mechanisms and downregulates the cellular response to the transport at gene levels, which works as a negative feedback loop and explains the higher cellular retention of GCPNs. These findings offer a solid foundation in the bile acid-based nanomedicine design, with utilizing advantages of the ASBT-mediated uptake, as well as inspiration to take comprehensive consideration of the cellular response with more developed technologies.

The Role of Di(2-Ethylhexyl) Phthalate as an Exacerbating Factor in Chronic Spontaneous Urticaria.

Phthalates are one of the most commonly used endocrine disruptors and have been considered a risk factor for respiratory disease including asthma. However, it is not yet known how they are related to urticaria. We investigated the association between phthalate exposure and urticaria in 10 healthy controls and 20 adult patients with active urticaria. The urinary levels of mono-n-butyl phthalate (MnBP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were measured by using high performance liquid chromatography tandem mass spectrometry, and mast cell releasability was determined after phthalate treatment. The levels of phthalate metabolites, especially di-ethylhexyl phthalate (DEHP), are significantly increased in the urine of patients with urticaria compared to the healthy controls. The release of ß-hexosaminidase in human mast cells is more significantly increased by MnBP, mono-benzyl phthalate, MEHHP, and MECPP compared to the negative controls; interestingly, the highest secretion of ß-hexosaminidase is observed after the lowest stimulation of MECPP. Phthalates, including DEHP, may act as aggravating factors for chronic spontaneous urticaria and can be used as potential therapeutic targets in future studies.

Increased serum free IgE levels in patients with chronic spontaneous urticaria (CSU).

Background: IgE bound on the surface of mast cells contributes to the pathogenesis of chronic spontaneous urticaria (CSU). Atopy is a predisposing factor for CSU, where omalizumab is a widely used monoclonal antibody to control urticaria symptoms via capturing serum free IgE. However, the role of serum free IgE is not clarified in CSU. The present study evaluated the clinical relevance of serum free IgE in patients with CSU. Methods: Eighty-eight patients with CSU and 76 healthy controls (HCs) were enrolled in this study. Serum total and Dermatophagoides pteronyssinus (Der p)-specific IgE levels were measured by ImmunoCAPs. The serum free IgE levels were measured by ELISA using a novel IgETRAP, and their associations with clinical parameters, including urticaria activity score (UAS), were evaluated. Changes in serum free and total IgE levels after omalizumab treatment were observed in 23 CSU patients in comparison between responders (≥50% reduction in UAS) and non-responders (<50% reduction). Results: Significantly higher serum free/total IgE levels were noted in CSU patients than in HCs with a positive correlation between the 2 values (rho = 0.87, P < 0.001). Among CSU patients, atopics had significantly higher serum free IgE levels than non-atopics, while no associations were noted with UAS, urticaria duration, or the results of serum ANA or autologous serum skin tests. In addition, there were no significant changes in serum free IgE levels during 12 months of omalizumab treatment. No significant differences were noted in serum free/total IgE levels or clinical parameters between responders and non-responders, while responders have higher serum Der p-specific IgE level and its ratio to serum free/total IgE level than non-responders (P < 0.05, respectively). Conclusions: These findings suggest that increased serum free IgE may be involved in the development of CSU by activating mast cells, especially in atopics. High Der p-specific IgE level and its ratio to serum free IgE level may be a potential biomarker for predicting favorable responses to omalizumab in CSU.

Down-regulated surfactant protein B in obese asthmatics.

BACKGROUND: Obesity is a common comorbid condition in adult asthmatics and known as a feature of asthma severity. However, the molecular mechanism under obesity-induced inflammation has not yet been fully understood. OBJECTIVE: Considering the essential role of hydrophobic surfactant protein B (SP-B) in lung function, SP-B was targeted to examine its involvement in the development of obesity-induced airway inflammation in asthmatics. METHODS: The aim was to examine an alteration in circulating SP-B according to obesity in adult asthmatics, 129 asthmatics were enrolled and classified into 3 groups (obese, overweight and normal-weight groups) according to body mass index (BMI). Circulating SP-B levels were determined by enzyme-linked immunosorbent assay. Four single nucleotide polymorphisms of SFTPB gene were genotyped. Serum ceramide levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Significantly lower serum SP-B levels were noted in the obese group than in the overweight or normal-weight group (p = .002). The serum SP-B level was significantly correlated with serum levels of C18:0 ceramide and transforming growth factor beta 1 as well as BMI (r = -0.200; r = -0.215; r = -0.332, p < .050 for all). An inverse correlation was noted between serum SP-B and fractional exhaled nitric oxide levels in female asthmatics (r = -0.287, p = .009). Genetic predisposition of the SFTPB gene at 9306 A>G to the obese and overweight groups was noted. CONCLUSION: Obesity altered ceramide metabolism leading to pulmonary surfactant dysfunction and impaired resolution of airway inflammation, finally contributing to the phenotypes of obese asthmatics.

Cereblon contributes to cardiac dysfunction by degrading Cav1.2α.

AIMS: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS: Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION: Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.