Publications

Cerebral ischemia/reperfusion injury (CIRI) commonly occurs during the treatment of ischemic stroke and leads to severe consequences, including neuronal death and permanent loss of motor function. Accurate differentiation between the ischemic penumbra (IP) and the ischemic core area is crucial for timely intervention. Multimodal MRI plays a crucial role in the early diagnosis and treatment evaluation of acute ischemic stroke. PANoptosis is a recently discovered form of programmed cell death including apoptosis, necroptosis, and pyroptosis. It has been implicated in neuronal loss during CIRI, especially through absent in melanoma 2 (AIM2). Melatonin (Mel) exerts neuroprotective effects; however, whether PANoptosis is the main cause of neuronal death in CIRI and whether Mel exerts anti-PANoptotic effects to rescue CIRI remain unclear. This study aimed to examine the effects of Mel on PANoptosis in the IP of rats with CIRI and to systematically investigate the underlying mechanisms using multimodal MRI combined with histopathologic techniques. A rat CIRI model comprising 42 healthy male Sprague-Dawley rats, weighing 240-270 g, was established using the modified Zea-Longa wire bolus method. Multimodal MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI)-MRI, and chemical exchange saturation transfer (CEST), was performed to evaluate the ischemic lesions and identify IP. T2WI, DWI-MRI, and tissue staining demonstrated that Mel significantly reduced infarct volume, improved neuron morphology, and decreased the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The IP was identified as the mismatch region between CEST and DWI-MRI, which was expanded by Mel treatment. In addition, Mel inhibited the expression of PANoptotic key proteins, as well as AIM2 expression, in IP neurons. In summary, multimodal MRI enables dynamic monitoring of IP after CIRI in vivo and effectively evaluates the neuroprotective effects of Mel on IP. Mel broadens the time window for CIRI rescue and exerts a neuroprotective effect by downregulating AIM2 expression in neurons, thereby suppressing PANoptotic neuronal death in the IP areas and alleviating brain injury in rats with CIRI.

A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model circulation-mediated crosstalk between the gut and brain. Using this system, we demonstrate gut-to-brain signaling by delivering bacterial-derived toxins to the gut compartment, which traverse the gut and neurovascular barriers and trigger neuroinflammatory responses and tau-associated pathology in the brain tissue. Conversely, we show that Alzheimer's- and Parkinson's-relevant stimuli applied to the brain compartment elicit neuroinflammation and disrupt both vascular and intestinal barrier integrity, indicating brain-to-gut feedback. Together, our platform provides a human-relevant tool to dissect mechanisms of bidirectional gut-brain communication and to evaluate therapeutic strategies for neurogastrointestinal disease.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is characterized by chronic progressive stenosis of intracranial vessels and subsequent formation of abnormal collateral vessel networks. Indirect revascularization techniques, such as encephalo-duro-arterio-synangiosis (EDAS), promote angiogenesis to restore perfusion but have variable success rates. This study aimed to identify clinical and radiographic predictors of successful collateral vessel ingrowth after EDAS, emphasizing the role of contralateral interhemispheric collaterals.

MATERIALS AND METHODS: We conducted a single-center retrospective analysis of cerebral hemispheres from adult MMD patients who underwent EDAS. We assessed demographic characteristics, clinical presentation, procedural details, clinical and radiographic outcomes. Angiographic outcomes were assessed using the Orbital Grading System. Univariate analysis was performed to identify factors associated with favorable postoperative collateral development. Consequently, preoperative contralateral interhemispheric collateralization was quantitatively evaluated through pixel density analysis on digital subtraction angiography (DSA), comparing the moyamoya-affected hemisphere to the contralateral hemisphere.

RESULTS: 61 MMD hemispheres of 43 adult patients were included in the study. Median times to last clinical and angiographic follow up were 29.9 months and 13.6 months, respectively. Higher Suzuki-stages (V and VI; p=<0.01), occlusions of the anterior cerebral artery (ACA; p=0.03) and internal carotid artery (ICA; p=0.048) were associated with superior postoperative collateralization. The presence of robust contralateral collaterals on preoperative angiography significantly predicted poor postoperative neovascularization (p=0.01). Pixel density analysis showed that increased pixel density ratios of moyamoya-affected hemisphere to contralateral hemisphere significantly correlated with reduced postoperative collateral vessel formation (Orbital Grading System, OR=130.94, p=0.008; Matsushima grading system, OR=52.09, p=0.018).

CONCLUSION: Higher Suzuki-stages, ACA and ICA occlusion predict successful neovascularization after EDAS. The presence of robust preoperative contralateral interhemispheric collaterals is an important predictor of poor collateral vessel ingrowth following EDAS. This finding suggests that such collateralization might reduce the local ischemic stimulus required for effective indirect revascularization. These findings could refine surgical decision-making by identifying patients who may be less likely to benefit from EDAS.

BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear.

OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma.

METHODS: We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677).

RESULTS: Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma.

CONCLUSIONS: Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.

BACKGROUND: Inborn errors of immunity are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals.

OBJECTIVE: We sought to investigate how 3 novel heterozygous variants in dedicator of cytokinesis 2 (DOCK2) contribute to impaired antiviral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal-recessive disease.

METHODS: After identifying the first DOCK2 variant, we screened 1109 exomes from 3 cohorts of patients with a history of at least 1 severe respiratory, blood-borne, or soft-tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary PBMCs and in cell-based overexpression systems.

RESULTS: Six individuals from 3 unrelated families, aged 3 months to 50 years, carried 1 of 3 heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in 1 patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency.

CONCLUSIONS: These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2-ELMO1 interactions impair protein stability and antiviral immunity, revealing a previously unrecognized inborn error of immunity affecting otherwise healthy individuals.

OBJECTIVE: Frailty occurs prematurely in rheumatoid arthritis (RA) and is associated with poor health outcomes. We compared the performance of four frailty instruments, including a pragmatic alternative measure using chair sit-to-stand (STS), and evaluated their abilities to predict poor health outcomes.

METHODS: Frailty was measured at baseline using four instruments: the Fried Frailty Phenotype with STS (Fried-STS), the Fried Frailty Phenotype with hand grip strength (Fried-HGS), the Veterans Affairs Frailty Index (VA-FI), and the FRAIL Scale. Outcomes collected at the one-year follow-up included category of falls (none, one, more than one), category of days hospitalized (none, one to three, more than three), and a composite outcome of fall, hospitalization, or death. Ordinal logistic or logistic regression models, adjusted for age and sex, explored the association of frailty and each outcome.

RESULTS: A total of 143 participants were included (mean ± SD age 64.5 ± 11.7 years, 73% male, and 69% White). Categorization as frail differed by instrument: Fried-STS, 17%; Fried-HGS, 15%; VA-FI, 36%; and FRAIL Scale, 20%. There was poor agreement between frailty instruments (k = 0.07-0.31) except for the Fried-STS and Fried-HGS (k = 0.62). Frailty by the Fried-STS, Fried-HGS, and FRAIL Scale was associated with falls (adjusted odds ratios [aORs] 3.83-9.54, P < 0.05). Frailty by the VA-FI was associated with days hospitalized (aOR 5.21, P = 0.017). Frailty by the Fried-STS, VA-FI, and FRAIL Scale was associated with higher odds of the composite measure of incident fall, hospitalization, or death (aORs 2.93-7.25, P < 0.05).

CONCLUSION: Each frailty measure predicted adverse health outcomes, with phenotypic and patient-reported measures predicting falls and the deficit accumulation model predicting hospitalization days. Being frail by the Fried-HGS did not predict poor outcomes as well as the other frailty instruments, including the Fried-STS.

Organ-on-a-chip (OoC) technology is a powerful tool for creating physiologically relevant microscale models applicable to biomedical studies. Despite the advances in OoC technology, its fabrication method still primarily relies on soft lithography, which has a long design-to-prototype cycle that creates a bottleneck in the acceleration of OoC innovation. To increase the agility of the OoC fabrication process, a system is developed to fabricate OoC using a digital photomask aligned with a microchamber. The approach uses a pre-defined microfluidic chamber customized by xurography and microfluidic channels photopatterned by a digital photomask. The versatility of the approach offered previously unattainable features in the fabrication of OoC, including non-reticular height profiles of the OoC architecture, and real-time modification of channel designs to trap suspension culture (e.g., spheroids). In summary, this work highlights a versatile system to fabricate OoC by direct photopatterning that can accommodate various OoC design requirements of microenvironments of specific organ tissues. It is anticipated that the system can facilitate the rapid fabrication of OoC, potentially supporting advancements in OoC design innovation, which can potentially increase the adoption of the OoC technology for therapeutic screening and elucidation of disease mechanisms in the scientific community.

Major depressive disorder (MDD) remains a highly heterogeneous condition, presenting significant challenges for effective diagnosis and treatment. Traditional diagnostic systems often fail to capture the diverse clinical and biological phenotypes of MDD, limiting the efficacy and predictability of therapeutic interventions. The advent of wearable technology has enabled the continuous collection of real-time, objective data. By leveraging advanced artificial intelligence (AI) methodologies, these data streams can be transformed into dynamic digital phenotypes that may correlate with the complex psychopathological manifestations of depression. This integration offers a novel, data-driven approach to augment traditional subjective assessments, paving the way for more precise classification and personalized treatment strategies. This review explores the potential of AI-enhanced digital phenotyping to revolutionize depression diagnosis and management, advocating for a paradigm shift toward a more personalized, precision-based approach in psychiatric practice.