Targeting TrkB-PSD-95 coupling to mitigate neurological disorders.

Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Long-term follow-up of symptom and quality of life changes in patients with narcolepsy during and after the COVID-19 pandemic.

The COVID-19 pandemic may have a significant impact on patients with narcolepsy, yet a long-term follow-up study is currently lacking. This study aims to investigate changes in symptom severity and the quality of life of patients with narcolepsy during and after the pandemic. Patients with type 1 or type 2 narcolepsy (NT1, NT2) were retrospectively recruited and prospectively followed from 2020 to 2023. They received evaluations including the Epworth Sleepiness Scale (ESS), the visual analog scale (VAS) for hypersomnolence, the VAS for cataplexy, the Short-form 36 Health Survey questionnaire (SF-36), and a sleep diary. We compared the differences between the pre-lockdown, the lockdown, the post-lockdown, and the post-pandemic periods by repeated measures ANOVA or the Friedman test, with the Bonferroni test for post hoc analysis. A total of 100 patients completed the 4-year study (mean age, 24.06 ± 7.00 years; 55% male). We observed significant differences in the ESS (p = 0.037), total nighttime sleep (p = 0.03), total sleep time (p = 0.035), and sleep efficiency (p = 0.035) during the study period. There was also significantly worse physical role functioning in the post-pandemic period (p = 0.014). In particular, the NT1 group had significantly decreased VAS-C scores (p < 0.001) but experienced worse physical role functioning in the post-pandemic period (p = 0.009). Patients with narcolepsy continue to face challenges after the pandemic. A more flexible lifestyle with an adequate sleep time may be beneficial, and medication adherence should be emphasized.

Diagnostic meta-analysis of the efficacy of ultrasonography for diagnosing carpal tunnel syndrome: A comparison between Asian and non-Asian populations.

BACKGROUND: Ultrasonography is used to diagnose carpal tunnel syndrome (CTS) according to various criteria. This diagnostic meta-analysis aimed to evaluate the efficacy of ultrasonography for diagnosing CTS, focusing on the cross-sectional area (CSA) of the median nerve (MN) at the inlet of the carpal tunnel and regional variations in diagnostic thresholds between Asian and non-Asian populations. METHODS: A comprehensive literature search was conducted using PubMed, Embase, and the Cochrane Library. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Patient demographic data, diagnostic "gold standards", CSA cutoff values, and diagnostic results were extracted. Meta-analysis was performed to determine the sensitivity, specificity, and optimal CSA cutoff values. RESULTS: For the 25 included studies, a combined sensitivity of 88% and specificity of 84% for CSA measurements at the carpal tunnel inlet were obtained. The Asian group had a sensitivity of 84% and specificity of 86%, while the non-Asian group had a sensitivity of 91% and specificity of 82%. The mean CSA in the Asian group was significantly lower than that in the non-Asian group (12.93 mm2 and 14.77 mm2, respectively; p = 0.042). For the Asian group, the summary receiver operating characteristic curve had an area under the curve (AUC) of 0.92 with an optimal cutoff of 10.5 mm2; for the non-Asian group, an AUC of 0.94 was obtained with a cutoff of 11.5 mm2. CONCLUSION: Ultrasonography is a reliable diagnostic method for CTS, with distinct optimal cutoff values observed between Asian and non-Asian populations. Therefore, population-specific diagnostic criteria for CTS are recommended.

Increased risks of retinal vascular occlusion in patients with migraine and the protective effects of migraine treatment: a population-based retrospective cohort study.

Associations between migraine and retinal vascular occlusion have been reported, but there is no large-scale and comprehensive study. Therefore, we aimed to determine risks of retinal vascular occlusion in patients with migraine. Using the Taiwan National Health Insurance Research Database from 2009 to 2020, we enrolled 628,760 patients with migraine and 628,760 matched individuals without migraine. Study outcomes were diagnoses of retinal vascular occlusion, including retinal artery occlusion (RAO) and retinal vein occlusion (RVO). Adjusted hazard ratio (aHR) of retinal vascular occlusion related to migraine was estimated. The cumulative incidences of subsequent retinal vascular occlusion, RAO, and RVO were significantly higher in migraine patients compared with controls (0.31% vs. 0.21%; 0.09% vs. 0.05%; 0.22% vs. 0.17%; all p < 0.001). The hazards of retinal vascular occlusion, RAO, and RVO were significantly greater in the migraine group (aHR, 1.69 [95% CI, 1.57, 1.83], 2.13 [95% CI, 1.84, 2.48] and 1.53 [95% CI, 1.40, 1.68], respectively). Risks of retinal vascular occlusion were significantly higher in migraine both with aura (MA) and without aura (MO) (aHR, 1.77 [95% CI, 1.58, 1.98], and 1.92 [95% CI, 1.64, 2.25]). Among patients with migraine, nonsteroidal anti-inflammatory drugs, propranolol, and flunarizine significantly reduce their risks of retinal vascular occlusion (aHR, 0.19 [95% CI, 0.16, 0.22], 0.73 [95% CI, 0.62, 0.86], 0.84 [95% CI, 0.76, 0.93]). Migraine, MA and MO are independently associated with higher risks of retinal vascular occlusion, RAO, and RVO.

Accelerometer-Measured Daily Behaviors That Mediate the Association Between Refractive Status and Depressive Disorders.

Purpose: To identify the accelerometer-measured daily behaviors that mediate the association of refractive status with depressive disorders and enhance the understanding of behavioral differences in depression. Methods: Participants with baseline mean spherical equivalent (MSE) and 7-day accelerometer measurements from the UK Biobank were included in this cohort study. Refractive status was categorized as hyperopia and non-hyperopia. Four daily behaviors, including moderate to vigorous intensity physical activity (MVPA), light physical activity (LPA), sedentary, and sleep were recorded between 2013 and 2015. We also assessed 24-hour behavior patterns. Depression cases were defined through both questionnaires and hospital records over 10 years of follow-up. Results: Among 20,607 individuals, every 0.5-diopter increase in MSE was associated with a 6% higher risk of depressive disorders, with hyperopia participants at a higher risk than non-hyperopia participants (odds ratio, 1.14; 95% confidence interval, 1.05-1.23; P = 0.001). MVPA and sleep time significantly correlated with depressive disorders, with odds ratios of 0.79 and 1.14 (P < 0.05). MSE showed significant correlations with all four behaviors. The effects of MVPA and sleep duration on MSE and depressive disorders varied throughout the day. Mediation analyses showed that MVPA and sleep partially mediated the relationship between MSE and depressive disorders, with 35.2% of the association between moderate to high hyperopia and depression mediated by MVPA. Conclusions: Physical activity and sleep significantly mediate the relationship between MSE and depressive disorders. Translational Relevance: The mediation effect of MVPA highlights its therapeutic potential in reducing the risk of depression among individuals with moderate to severe hyperopia. Interventions aimed at increasing daytime MVPA and decreasing daytime sleep could enhance mental health in this vulnerable group.

High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.

BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.

Determination of 16 ultraviolet-absorbing compounds in marine invertebrates by using LC-USI-MS/MS coupled with QuEChERS.

In this study, we examined multiple endocrine-disrupting ultraviolet-absorbing compounds (UVACs) in marine invertebrates used in personal care products and packaging. Modified QuEChERS and liquid chromatography UniSpray ionization tandem mass spectrometry were used to identify 16 UVACs in marine invertebrates. Matrix-matched calibration curves revealed high linearity (r ≥ 0.9929), with limits of detection and quantification of 0.006-1.000 and 0.020-3.000 ng/g w.w., respectively. In oysters, intraday and interday analyses revealed acceptable accuracy (93%-120%) and precision (≤18%), except for benzophenone (BP) and ethylhexyl 4-(dimethylamino) benzoate. Analysis of 100 marine invertebrate samples revealed detection frequencies of 100%, 98%, 89%, 64%, and 100% for BP, 4-hydroxybenzophenone, 4-methylbenzophenone, 4-methylbenzylidene camphor, and benzophenone-3 (BP-3), respectively. BP and BP-3 were detected at concentrations of 4.40-27.39 and < 0.020-0.560 ng/g w.w., respectively, indicating their widespread presence. Overall, our proposed method successfully detected UVACs in marine invertebrates, raising concerns regarding their potential environmental and health effects.

Association of retinal age gap with chronic kidney disease and subsequent cardiovascular disease sequelae: a cross-sectional and longitudinal study from the UK Biobank.

Background: Chronic kidney disease (CKD) increases the risk of cardiovascular disease (CVD) and is more prevalent in older adults. Retinal age gap, a biomarker of aging based on fundus images, has been previously developed and validated. This study aimed to investigate the association of retinal age gap with CKD and subsequent CVD complications. Methods: A deep learning model was trained to predict the retinal age using 19 200 fundus images of 11 052 participants without any medical history at baseline. Retinal age gap, calculated as retinal age predicted minus chronological age, was calculated for the remaining 35 906 participants. Logistic regression models and Cox proportional hazards regression models were used for the association analysis. Results: A total of 35 906 participants (56.75 ± 8.04 years, 55.68% female) were included in this study. In the cross-sectional analysis, each 1-year increase in retinal age gap was associated with a 2% increase in the risk of CKD prevalence [odds ratio 1.02, 95% confidence interval (CI) 1.01-1.04, P = .012]. A longitudinal analysis of 35 039 participants demonstrated that 2.87% of them developed CKD in follow-up, and each 1-year increase in retinal age gap was associated with a 3% increase in the risk of CKD incidence (hazard ratio 1.03, 95% CI 1.01-1.05, P = .004). In addition, a total of 111 CKD patients (15.81%) developed CVD in follow-up, and each 1-year increase in retinal age gap was associated with a 10% increase in the risk of incident CVD (hazard ratio 1.10, 95% CI 1.03-1.17, P = .005). Conclusions: We found that retinal age gap was independently associated with the prevalence and incidence of CKD, and also associated with CVD complications in CKD patients. This supports the use of this novel biomarker in identifying individuals at high risk of CKD and CKD patients with increased risk of CVD.

Non-contact elasticity contrast imaging using photon counting.

Significance: Tissues' biomechanical properties, such as elasticity, are related to tissue health. Optical coherence elastography produces images of tissues based on their elasticity, but its performance is constrained by the laser power used, working distance, and excitation methods. Aim: We develop a new method to reconstruct the elasticity contrast image over a long working distance, with only low-intensity illumination, and by non-contact acoustic wave excitation. Approach: We combine single-photon vibrometry and quantum parametric mode sorting (QPMS) to measure the oscillating backscattered signals at a single-photon level and derive the phantoms' relative elasticity. Results: We test our system on tissue-mimicking phantoms consisting of contrast sections with different concentrations and thus stiffness. Our results show that as the driving acoustic frequency is swept, the phantoms' vibrational responses are mapped onto the photon-counting histograms from which their mechanical properties-including elasticity-can be derived. Through lateral and longitudinal laser scanning at a fixed frequency, a contrast image based on samples' elasticity can be reliably reconstructed upon photon level signals. Conclusions: We demonstrated the reliability of QPMS-based elasticity contrast imaging of agar phantoms in a long working distance, low-intensity environment. This technique has the potential for in-depth images of real biological tissue and provides a new approach to elastography research and applications.

A scheme of hiding large-size image into small-size image based on FCdDNet.

The hiding capacity of the current information hiding field has reached a relatively high level, which can hide two color images into one color image. In order to explore a larger hidden capacity, an information hiding scheme based on an improved FCdDNet is proposed, which can hide large-size color images into small-size color images. An improved FCdDNet network is used as the main structure shared by the hidden network and the extraction network. These two networks promote and improve each other during the confrontation training process and are used in pairs. It can be seen that the proposed scheme achieves a larger information hiding capacity, and the hidden information is four times larger than the scale of the carrier image. At the same time, the visual effect after hiding is guaranteed, and the image extracted from the hidden image also has a high degree of restoration. The scheme can be applied to image authentication, secret image transmission, and other fields.

Peritoneal fluid indocyanine green test for diagnosis of gut leakage in anastomotic leakage rats and colorectal surgery patients.

BACKGROUND: Application of indocyanine green (ICG) fluorescence has led to new developments in gastrointestinal surgery. However, little is known about the use of ICG for the diagnosis of postoperative gut leakage (GL). In addition, there is a lack of rapid and intuitive methods to definitively diagnose postoperative GL. AIM: To investigate the effect of ICG in the diagnosis of anastomotic leakage in a surgical rat GL model and evaluate its diagnostic value in colorectal surgery patients. METHODS: Sixteen rats were divided into two groups: GL group (n = 8) and sham group (n = 8). Approximately 0.5 mL of ICG (2.5 mg/mL) was intravenously injected postoperatively. The peritoneal fluid was collected for the fluorescence test at 24 and 48 h. Six patients with rectal cancer who had undergone laparoscopic rectal cancer resection plus enterostomies were injected with 10 mL of ICG (2.5 mg/mL) on postoperative day 1. Their ostomy fluids were collected 24 h after ICG injection to identify the possibility of the ICG excreting from the peripheral veins to the enterostomy stoma. Participants who had undergone colectomy or rectal cancer resection were enrolled in the diagnostic test. The peritoneal fluids from drainage were collected 24 h after ICG injection. The ICG fluorescence test was conducted using OptoMedic endoscopy along with a near-infrared fluorescent imaging system. RESULTS: The peritoneal fluids from the GL group showed ICG-dependent green fluorescence in contrast to the sham group. Six samples of ostomy fluids showed green fluorescence, indicating the possibility of ICG excreting from the peripheral veins to the enterostomy stoma in patients. The peritoneal fluid ICG test exhibited a sensitivity of 100% and a specificity of 83.3% for the diagnosis of GL. The positive predictive value was 71.4%, while the negative predictive value was 100%. The likelihood ratios were 6.0 for a positive test result and 0 for a negative result. CONCLUSION: The postoperative ICG test in a drainage tube is a valuable and simple technique for the diagnosis of GL. Hence, it should be employed in clinical settings in patients with suspected GL.

Miniaturized 3D-printed hand-operable dispersive sample pretreatment device with replaceable chitosan/polydopamine thin film metal sorbent for enhanced metal analysis.

To address the increasing demand for sensitive and selective sample preparation methods for metal analysis; preconcentration of intended analyte from complex sample matrices before analysis is required to improve the performance of analysis instruments. In this study, we have engineered a sustainable and portable syringe-based hand-operable three-dimensionally (3D) printed sample pretreatment apparatus equipped with a replaceable bio-based thin- film metal sorbent. This device effectively addresses the challenges of sample matrix interference in metal analysis. A metal sorbent film composed of chitosan (CS) and polydopamine (PDA) leveraged the diverse functional groups in the CS/PDA matrix to significantly enhance the extraction efficiency for various metals. Our approach demonstrated excellent analytical performance, with coefficients of determination (R2) of 0.9982 for copper (Cu) and 0.996 for chromium (Cr). The method achieved low limits of detection (LOD) of 0.3 µg L-1 for Cr and 0.7 µg L-1 for Cu. Precision and practicality assessments using actual urine samples yielded satisfactory relative standard deviations (RSD%) ranging from of 1.6 %-8.5 % for both metals, indicating minimal interference from the sample matrix. Moreover, our approach exhibited robust performance even after seven consecutive extraction and desorption cycles, highlighting its sustainability and practical applicability for laboratory and on-site sample pretreatment.

Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease.

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

The Impact of Close Proximity of Left Atrium to Descending Aorta on Left Inferior Pulmonary Vein Triggers or Drivers of Atrial Fibrillation: A Risk Score Model.

BACKGROUND: Prior studies have investigated cardiac anatomy and clinical parameters as predictors for pulmonary vein and non-pulmonary vein triggers. OBJECTIVES: To assess the link between the descending aorta to left inferior pulmonary vein (Dao-LIPV) distance and the occurrence of triggers and drivers in atrial fibrillation (AF) ablation procedures. METHODS: Drug-refractory AF patients who underwent first-time index catheter ablation from January 2010 to December 2019 were retrospectively assembled. The Dao-LIPV distance was measured from pre-ablation pulmonary vein computed tomography. Patients were categorized based on the presence of LIPV triggers and/or drivers. Multivariate logistic regression was used to identify risk factors. RESULTS: A total of 886 consecutive patients with drug-refractory AF were studied, and 63 (7.1%) patients were identified to have LIPV triggers and/or drivers. The Dao-LIPV distance had a better predictive performance (AUC: 0.70) compared to persistent AF (AUC: 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤ 2.5 mm (Odds ratio [OR] 3.96 [95% CI 2.15-7.29], p <0.001) and persistent AF (OR 1.73 [95% CI 1.02-2.94], p=0.044) were independent predictors for the presence of LIPV triggers and/or drivers. A risk score model was established to predict the probability of LIPV triggers or drivers with persistent AF (10.2%), Dao-LIPV distance ≤ 2.5mm (11.4%), and both (15.0%). CONCLUSIONS: The close proximity of the Dao-LIPV was correlated to the presence of LIPV triggers or drivers. We developed a risk score model indicating that persistent AF and Dao-LIPV distances ≤ 2.5mm significantly increase the risk of LIPV triggers/drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively.

Metabolic profiling reveals circulating biomarkers associated with incident and prevalent Parkinson's disease.

The metabolic profile predating the onset of Parkinson's disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P < 0.05), spanning lipids, lipid constituent of lipoprotein subclasses and ratios of lipid constituents. After multiple testing corrections (P < 9 × 10-4), polyunsaturated fatty acids (PUFA) and omega-6 fatty acids remained significantly associated with incident PD, and PUFA was shared by incident and prevalent PD. Additionally, 14 metabolites were exclusively associated with prevalent PD, including amino acids, fatty acids, several lipoprotein subclasses and ratios of lipids. Adding these metabolites to the conventional risk factors yielded a comparable predictive performance to the risk-factor-based model (AUC = 0.766 vs AUC = 0.768, P = 0.145). Our findings suggested metabolic profiles provided additional knowledge to understand different pathways related to PD before and after its onset.

Fully Optical Control of Polarization Current Direction in a Cyanide-Bridged Trinuclear Complex.

As a remote and non-contact stimulus, light offers the potential for manipulating the polarization of ferroelectric materials without physical contact. However, in current research, the non-contact write-read (erase) process lacks direct observation through the stable current as output signal. To address this limitation, we investigated the photoinduced polarization switching capabilities of the cyanide-bridged compound [Fe2Co] using visible light, leading to the achievement of rewritable polarization. By subjecting [Fe2Co] crystals to alternating irradiation with 785 nm and 532 nm light, the polarization changes exhibited a distinct square wave pattern, confirming the reliability of the writing and erasing processes. Initialization involved exposing specific crystal units to 532 nm light for storing "1" or "0" information, while reading was accomplished by scanning the units with 785 nm light, resulting in brief current pulses for "1" states and no current signal for "0" states. This research unveils new possibilities for optical storage systems, paving the way for efficient and rewritable data storage and retrieval technologies, such as the next-generation memories.

Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CCHD) with multifactorial etiology. We aimed to investigate the metabolic profiles of CCHD and their independent contributions to TOF. METHODS: A cohort comprising 42 individuals with TOF and atrial septal defect (ASD) was enrolled. Targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to systematically analyze metabolite levels and identify TOF-associated metabolic profiles. RESULTS: Of 370 identified metabolites in tissue and 284 in plasma, over one-third of metabolites showed an association with microbiome. Differential metabolic pathways including amino acids biosynthesis, ABC (ATP-binding cassette) transporters, carbon metabolism, and fatty acid biosynthesis, shed light on TOF biological phenotypes. Additionally, ROC curves identified potential biomarkers, such as erythronic acid with an AUC of 0.868 in plasma, and 3-ß-hydroxy-bisnor-5-cholenic acid, isocitric acid, glutaric acid, ortho-Hydroxyphenylacetic acid, picolinic acid with AUC close to 1 in tissue, whereas the discriminative performance of those substances significantly improved when combined with clinical phenotypes. CONCLUSIONS: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing TOF from ASD patients. These metabolites may serve as biomarkers or key molecular players in the intricate metabolic pathways involved in CCHD development. IMPACT: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing Tetralogy of Fallot from atrial septal defect patients. Similar profiling but inconsistent differential pathways between plasma and tissue. More than one-third metabolites in plasma and tissue are associated with the microbiome. The discovery of biomarkers is instrumental in facilitating early detection and diagnosis of Tetralogy of Fallot. Disturbed metabolism offers insights into interpretation of pathogenesis of Tetralogy of Fallot.

SIVA-1 interaction with PCBP1 serves as a predictive biomarker for cisplatin sensitivity in gastric cancer and its inhibitory effect on tumor growth in vivo.

Background: SIVA-1 has been reported to play a key role in cell apoptosis and gastric cancer (GC) chemoresistance in vitro. Nevertheless, the clinical significance of SIVA-1 in GC chemotherapy remains unclear. Methods and results: Immunohistochemistry and histoculture drug response assays were used to determine SIVA-1 expression and the inhibition rate (IR) of agents to GC and to further analyze the relationship between these two phenomena. Additionally, cisplatin (DDP)-resistant GC cells were used to elucidate the role and mechanism of SIVA-1 in vivo. The results demonstrated that SIVA-1 expression was positively correlated with the IR of DDP to GC but not with those of 5-fluorouracil (5-FU) or adriamycin (ADM). Furthermore, SIVA-1 overexpression with DDP treatment synergistically inhibited tumor growth in vivo by increasing PCBP1 and decreasing Bcl-2 and Bcl-xL expression. Conclusions: Our study demonstrated that SIVA-1 may serve as an indicator of the GC sensitivity to DDP, and the mechanism of SIVA-1 in GC resistance to DDP was preliminarily revealed.

Genome-Scale Multimodal Analysis of Cell-Free DNA Whole-Methylome Sequencing for Noninvasive Esophageal Cancer Detection.

PURPOSE: Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS: Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS: ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION: This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

Effects of edge disorder on the stability of quantum oscillations in two-dimensional coupled systems.

This paper utilizes the theory of quantum diffusion to analyze the electron probability and spreading width of a wavepacket on each layer in a two-dimensional (2D) coupled system with edge disorder, aiming to clarify the effects of edge disorder on the stability of the electron periodic oscillations in 2D coupled systems. Using coupled 2D square lattices with edge disorder as an example, we show that, the electron probability and wavepacket spreading width exhibit periodic oscillations and damped oscillations, respectively, before and after the wavepacket reaches the boundary. Furthermore, these electron oscillations exhibit strong resistance against disorder perturbation with a longer decay time in the regime of large disorder, due to the combined influences of ordered and disordered site energies in the central and edge regions. Finally, we numerically verified the universality of the results through bilayer graphene, demonstrating that this anomalous quantum oscillatory behavior is independent of lattice geometry. Our findings are helpful in designing relevant quantum devices and understanding the influence of edge disorder on the stability of electron periodic oscillations in 2D coupled systems.