Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.

Corrective feedback guides human perceptual decision-making by informing about the world state rather than rewarding its choice.

Corrective feedback received on perceptual decisions is crucial for adjusting decision-making strategies to improve future choices. However, its complex interaction with other decision components, such as previous stimuli and choices, challenges a principled account of how it shapes subsequent decisions. One popular approach, based on animal behavior and extended to human perceptual decision-making, employs "reinforcement learning," a principle proven successful in reward-based decision-making. The core idea behind this approach is that decision-makers, although engaged in a perceptual task, treat corrective feedback as rewards from which they learn choice values. Here, we explore an alternative idea, which is that humans consider corrective feedback on perceptual decisions as evidence of the actual state of the world rather than as rewards for their choices. By implementing these "feedback-as-reward" and "feedback-as-evidence" hypotheses on a shared learning platform, we show that the latter outperforms the former in explaining how corrective feedback adjusts the decision-making strategy along with past stimuli and choices. Our work suggests that humans learn about what has happened in their environment rather than the values of their own choices through corrective feedback during perceptual decision-making.

Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice.

Mutations in the Presenilin (PSEN1 and PSEN2) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD PSEN1 mutations exhibit impaired γ-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing γ-secretase activity and is located closest to the active site of γ-secretase. Here, we report that introduction of the codon-optimized wild-type human PSEN1 cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired γ-secretase activity in the cerebral cortex of Psen mutant mice either lacking PS or expressing the Psen1 L435F KI allele, as evaluated by endogenous γ-secretase substrates of APP and recombinant γ-secretase products of Notch intracellular domain and Aß peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in Psen mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged Psen mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired γ-secretase activity, synaptic and memory deficits, and neurodegeneration caused by Psen mutations in mouse models.

Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease.

Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.

Neural Evidence for Boundary Updating as the Source of the Repulsive Bias in Classification.

Binary classification, an act of sorting items into two classes by setting a boundary, is biased by recent history. One common form of such bias is repulsive bias, a tendency to sort an item into the class opposite to its preceding items. Sensory-adaptation and boundary-updating are considered as two contending sources of the repulsive bias, yet no neural support has been provided for either source. Here, we explored human brains of both men and women, using functional magnetic resonance imaging (fMRI), to find such support by relating the brain signals of sensory-adaptation and boundary-updating to human classification behavior. We found that the stimulus-encoding signal in the early visual cortex adapted to previous stimuli, yet its adaptation-related changes were dissociated from current choices. Contrastingly, the boundary-representing signals in the inferior-parietal and superior-temporal cortices shifted to previous stimuli and covaried with current choices. Our exploration points to boundary-updating, rather than sensory-adaptation, as the origin of the repulsive bias in binary classification.SIGNIFICANCE STATEMENT Many animal and human studies on perceptual decision-making have reported an intriguing history effect called "repulsive bias," a tendency to classify an item as the opposite class of its previous item. Regarding the origin of repulsive bias, two contending ideas have been proposed: "bias in stimulus representation because of sensory adaptation" versus "bias in class-boundary setting because of belief updating." By conducting model-based neuroimaging experiments, we verified their predictions about which brain signal should contribute to the trial-to-trial variability in choice behavior. We found that the brain signal of class boundary, but not stimulus representation, contributed to the choice variability associated with repulsive bias. Our study provides the first neural evidence supporting the boundary-based hypothesis of repulsive bias.

In Vivo Dynamic and Static Analysis of Lymphatic Dysfunction in Lymphedema Using Near-Infrared Fluorescence Indocyanine Green Lymphangiography.

BACKGROUND: Near-infrared fluorescence indocyanine green lymphangiography, a primary modality for detecting lymphedema, which is a disease due to lymphatic obstruction, enables real-time observations of lymphatics and reveals not only the spatial distribution of drainage (static analysis) but also information on the lymphatic contraction (dynamic analysis). METHODS: We have produced total lymphatic obstruction in the upper limbs of 18 Sprague-Dawley rats through the dissection of proximal (brachial and axillary) lymph nodes and 20-Gy radiation (dissection limbs). After the model formation for 1 week, 9 animal models were observed for 6 weeks using near-infrared fluorescence indocyanine green lymphangiography by injecting 6-µL ICG-BSA (indocyanine green-bovine serum albumin) solution of 20-µg/mL concentration. The drainage pattern and leakage of lymph fluid were evaluated and time-domain signals of lymphatic contraction were observed in the distal lymphatic vessels. The obtained signals were converted to frequency-domain spectrums using signal processing. RESULTS: The results of both static and dynamic analyses proved to be effective in accurately identifying the extent of lymphatic disruption in the dissection limbs. The static analysis showed abnormal drainage patterns and increased leakage of lymph fluid to the periphery of the vessels compared with the control (normal) limbs. Meanwhile, the waveforms were changed and the contractile signal frequency increased by 58% in the dynamic analysis. Specifically, our findings revealed that regular lymphatic contractions, observed at a frequency range of 0.08 to 0.13 Hz in the control limbs, were absent in the dissection limbs. The contractile regularity was not fully restored for the follow-up period, indicating a persistent lymphatic obstruction. CONCLUSIONS: The dynamic analysis could detect the abnormalities of lymphatic circulation by observing the characteristics of signals, and it provided additional evaluation indicators that cannot be provided by the static analysis. Our findings may be useful for the early detection of the circulation problem as a functional evaluation indicator of the lymphatic system.

Center of Pressure- and Machine Learning-based Gait Score and Clinical Risk Factors for Predicting Functional Outcome in Acute Ischemic Stroke.

OBJECTIVES: To investigate whether machine learning (ML)-based center of pressure (COP) analysis for gait assessment, when used in conjunction with clinical information, offers additive benefits in predicting functional outcomes in patients with acute ischemic stroke. DESIGN: A prospective, single-center cohort study. SETTING: A tertiary hospital setting. PARTICIPANTS: A total of 185 patients with acute ischemic stroke, capable of walking 10 m with or without a gait aid by day 7 postadmission. From these patients, 10,804 pairs of consecutive footfalls were included for analysis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The dependent variable was a 3-month poor functional outcome, defined as modified Rankin scale score ≥2. For independent variables, 65 clinical variables including demographics, anthropometrics, comorbidities, laboratory data, questionnaires, and drug history were included. Gait function was evaluated using a pressure-sensitive mat. Time-series COP data were parameterized into spatial and temporal variables and analyzed with logistic regression and 2 ML models (light gradient-boosting machine and multilayer perceptron [MLP]). We derived GAIT-AI output scores from the best-performing model analyzed COP data and constructed multivariable logistic regression models using clinical variables and the GAIT scores. RESULTS: Among the included patients, 70 (37.8%) experienced unfavorable outcomes. The MLP model demonstrated the highest predictive performance with an area under the receiver operating characteristic curve (AUROC) of 0.799. Multivariable logistic regression identified age, initial National Institutes of Health Stroke Scale, and initial Fall Efficacy Scale-International as associated factors with unfavorable outcomes. The combined multivariable logistic regression incorporating COP-derived output scores improved the AUROC to 0.812. CONCLUSIONS: Gait function, assessed through COP analysis, serves as a significant predictor of functional outcome in patients with acute ischemic stroke. ML-based COP analysis, when combined with clinical data, enhances the prediction of poor functional outcomes.

Variations in Risk Factors across Different Periods of Stroke and Transient Ischemic Attack Recurrence.

INTRODUCTION: Accurately discerning periods of heightened risk of stroke or transient ischemic attack (TIA) recurrence and managing modifiable risk factors are essential for minimizing overall recurrence risk. This study identified differences in the timing of stroke or TIA recurrence based on risk factors and patient characteristics to develop strategies for reducing recurrence in clinical practice. METHODS: We retrospectively selected patients with ischemic stroke or TIA at the Korea University Ansan Hospital Stroke Center between March 2014 and December 2021 using the prospective institutional database of the Korea University Stroke Registry. We collected demographic, clinical data, and categorized participants by recurrence timing (early within or late after 3 months). Using multinomial logistic regression analysis, we examined variables associated with early and late recurrent stroke or TIAs. RESULTS: Among 3,646 patients, 255 experienced a recurrent stroke or TIA and 3,391 experienced their first stroke or TIA. Multinomial logistic regression analysis revealed significant associations between early recurrent stroke or TIA and diabetes mellitus (odds ratio [OR]: 1.98, 95% confidence interval [CI]: 1.25-3.15), other determined etiologies in the Trial of Org 10172 in the Acute Stroke Treatment classification (OR: 3.00, 95% CI: 1.37-6.61), and white matter changes (OR: 1.97, 95% CI: 1.17-3.33). Late recurrence showed a significant correlation with TIA (OR: 2.95, 95% CI: 1.52-5.71) and cerebral microbleeds (OR: 2.22, 95% CI: 1.32-3.75). CONCLUSION: Substantial differences in factors contribute to stroke or TIA recurrence based on timing. Managing the risk of recurrence in clinical practice necessitates accurate identification of heightened risk periods and rigorous control of modifiable risk factors.

Impact of the life-sustaining treatment decision act on organ donation in out-of-hospital cardiac arrests in South Korea: a multi-centre retrospective study.

BACKGROUND: The demand for organ transplants, both globally and in South Korea, substantially exceeds the supply, a situation that might have been aggravated by the enactment of the Life-Sustaining Treatment Decision Act (LSTDA) in February 2018. This legislation may influence emergency medical procedures and the availability of organs from brain-dead donors. This study aimed to assess LSTDA's impact, introduced in February 2018, on organ donation status in out-of-hospital cardiac arrest (OHCA) patients in a metropolitan city and identified related factors. METHODS: We conducted a retrospective analysis of a regional cardiac arrest registry. This study included patients aged 16 or older with cardiac arrest and a cerebral performance category (CPC) score of 5 from January 2015 to December 2022. The exclusion criteria were CPC scores of 1-4, patients under 16 years, and patients declared dead or transferred from emergency departments. Logistic regression analysis was used to analyse factors affecting organ donation. RESULTS: Of the 751 patients included in this study, 47 were organ donors, with a median age of 47 years. Before the LSTDA, there were 30 organ donations, which declined to 17 after its implementation. In the organ donation group, the causes of cardiac arrest included medical (34%), hanging (46.8%), and trauma (19.2%). The adjusted odds ratio for organ donation before the LSTDA implementation was 6.12 (95% CI 3.09-12.12), with non-medical aetiology as associated factors. CONCLUSION: The enactment of the LSTDA in 2018 in South Korea may be linked to reduced organ donations among patients with OHCA, underscoring the need to re-evaluate the medical and legal aspects of organ donation, especially considering end-of-life care decisions.

High-frequency ultrasound-assisted perforator mapping enhances efficiency in microsurgical reconstruction using thin ALT and SCIP flaps.

BACKGROUND: With the growing demand for the use of thin perforator flaps, obtaining knowledge on the superficial anatomy of perforators is imperative for stable flap elevation. Conventional modalities for perforator mapping fall short in providing such information. High-frequency ultrasound (HFUS), known for visualizing the superficially located anatomic structures, may potentially fill this void. This study aimed to evaluate the effectiveness of HFUS in the outcome of anterolateral thigh (ALT) and superficial circumflex iliac artery perforator (SCIP) flap-based reconstructions. METHODS: Consecutive patients who underwent free ALT or SCIP flap-based reconstruction from January 2021 to November 2022 were retrospectively reviewed. Perforator mapping was conducted using a handheld Doppler during the first year, while HFUS was used in the latter part. The two techniques were compared in terms of flap harvesting time and perfusion-related complication rates while considering the flap elevation plane. RESULTS: In total, 123 cases were analyzed, including 82 ALT flaps (41 in each group) and 41 SCIP flaps (16 in the Doppler and 25 in the HFUS group). The time required for flap elevation exhibited a tendency to decrease in the HFUS group, with a significant difference observed in cases involving thin flap elevation (super-thin ALT flaps and pure-skin-perforator SCIP flaps). Compared with the Doppler group, the HFUS group demonstrated significantly lower rates of PRCs, particularly partial flap necrosis. This difference remained significant in multivariable analyses. CONCLUSION: Our results suggest that HFUS might be an appealing modality for perforator mapping in cases requiring thin ALT and SCIP flap.