Prolonged Signal Research Articles

Impaired Reactive Control But Preserved Proactive Control in Hyperactive Children

Objective: To examine the manifestation of cognitive control deficit of children with different levels of hyperactivity, an “at risk” dimension for ADHD. Method: A group of children with high hyperactivity (N = 40) and another group of children with low levels of hyperactivity (N = 38) performed a modified stop-signal anticipation task, a revised Go/NoGo task, and the AX-continuous performance test (AX-CPT). Results: Children with higher levels of hyperactivity displayed: (1) significantly prolonged stop signal reaction time (SSRT) in the modified stop-signal anticipation task; (2) no notable differences in commission errors in the revised Go/NoGo task; (3) increased reaction time (RT) in stop-signal task and Go/NoGo task with increased probabilities of stop or NoGo signal; and (4) positive proactive behavioral index scores in AX-CPT. Conclusion: The results suggested that children with heightened hyperactivity exhibited impaired reactive control, especially for responses already underway, but preserved proactive control. Further studies concerning these children are warranted.

Magnetic Porous Hydrogel-Enhanced Wearable Patch Sensor for Sweat Zinc Ion Monitoring.

Wearable sensors for sweat trace metal monitoring have the challenges of effective sweat collection and the real-time recording of detection signals. The existing detection technologies are implemented by generating enough sweat through exercise, which makes detecting trace metals in sweat cumbersome. Generally, it takes around 20 min to obtain enough sweat, resulting in dallied and prolonged detection signals that cannot reflect the endogenous fluctuations of the body. To solve these problems, we prepared a multifunctional hydrogel as an electrolyte and combined it with a flexible patch electrode to realize real-time monitoring of sweat Zn2+. Such hydrogel has magnetic and porous properties, and the porous structure of hydrogel enables a fast absorption of sweat, and the magnetic property of the addition of fabricated Fe3O4 NPs not only improves the conductivity but also ensures the adjustable internal structures of the hydrogel. Such a sensing platform for sweat Zn2+ monitoring shows a satisfied linear relationship in the concentration range of 0.16-16 µg/mL via differential pulsed anodic striping voltammetry (DPASV) and successfully detects the sweat Zn2+ of four volunteers during exercise and resting, displaying a promising path for commercial application.

Enzymatically stable, non-cell adhesive, implantable polypyrrole/thiolated hyaluronic acid bioelectrodes for in vivo signal recording

Implantable bioelectrodes have attracted significant attention for precise in vivo signal transduction with living systems. Conductive polymers, including polypyrrole (PPy), have been widely used as bioelectrodes due to their large surface areas, high charge injections, and versatilities for modification. Especially, several natural biopolymers, such as hyaluronic acid (HA), can be incorporated into conductive polymers to produce biomimetic electrodes with better biocompatibility. However, HA-incorporated PPy electrodes (PPy/HA) frequently lose their original performances after implantation in the body because of the deterioration of material properties, such as degradation of natural biopolymers in the electrode. Here, thiolated HA (HA–SH) was synthesized and introduced into PPy electrodes (PPy/HA–SH) to enhance the enzymatic stabilities of PPy electrodes against hyaluronidase (HAase) and endow these electrodes with robust resistances to non-specific cell adhesion, thereby enabling prolonged signal transmission. Unlike PPy/HA, PPy/HA–SH resisted cell adhesion even in the presence of HAase. Subcutaneous implantation studies revealed that PPy/HA–SH formed less fibrotic scar tissue and permitted more sensitive and stable signal recording for up to 15 days after implantation as compared to PPy/HA. These findings hold significance for the design and advancement of biocompatible implantable bioelectrodes for a wide range of applications, such as neural electrodes, cardiac pacemakers, and biosensors.

Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2.

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti-cancer therapies. The limitations of ATP-competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50=2.3nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor-promoting macrophage M2 phenotype in vitro and in vivo. In macrophage-rich tumor model, compound 11 notably slowed growth in a dose-dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.

Therapeutic potentials of nonpeptidic V2R agonists for partial cNDI-causing V2R mutants.

Loss-of-function mutations in the type 2 vasopressin receptor (V2R) are a major cause of congenital nephrogenic diabetes insipidus (cNDI). In the context of partial cNDI, the response to desmopressin (dDAVP) is partially, but not entirely, diminished. For those with the partial cNDI, restoration of V2R function would offer a prospective therapeutic approach. In this study, we revealed that OPC-51803 (OPC5) and its structurally related V2R agonists could functionally restore V2R mutants causing partial cNDI by inducing prolonged signal activation. The OPC5-related agonists exhibited functional selectivity by inducing signaling through the Gs-cAMP pathway while not recruiting β-arrestin1/2. We found that six cNDI-related V2R partial mutants (V882.53M, Y1283.41S, L1614.47P, T2736.37M, S3298.47R and S3338.51del) displayed varying degrees of plasma membrane expression levels and exhibited moderately impaired signaling function. Several OPC5-related agonists induced higher cAMP responses than AVP at V2R mutants after prolonged agonist stimulation, suggesting their potential effectiveness in compensating impaired V2R-mediated function. Furthermore, docking analysis revealed that the differential interaction of agonists with L3127.40 caused altered coordination of TM7, potentially contributing to the functional selectivity of signaling. These findings suggest that nonpeptide V2R agonists could hold promise as potential drug candidates for addressing partial cNDI.

High-Throughput Acoustic Ejection Mass Spectrometry with Adjustable Signal Durations.

High-throughput mass spectrometry (MS) has witnessed rapid advancements and has found extensive applications across various disciplines. It enables the fast and accurate analysis of large sample sets, delivering a 10-fold or greater enhancement in analytical throughput when compared to conventional LC-MS methods. However, the signal duration in these high-throughput MS technologies is typically confined to a narrow range, presenting challenges for workflows demanding prolonged signal durations. In this study, we introduce a method that enables precise modulation of the signal duration on an acoustic ejection mass spectrometry (AEMS) system while ensuring high signal reproducibility. This flexibility allows for simultaneous and precise analysis of a significantly greater number of MS/MS transitions in high-throughput MS environments. Additionally, it offers a unique approach for parameter optimization and method development with minimal sample volume requirements. This advancement enhances the efficiency of MS-based analyses across diverse applications and facilitates broader utilization of MS technologies in high-throughput settings, including data-dependent acquisition (DDA) and data-independent acquisition (DIA).

Misleading clinical and imaging features in atypical aggressive angiomyxoma of the female vulvovaginal or perianal region: report of three cases and review of the literature.

Aggressive (deep) angiomyxoma (AAM) is a rare mesenchymal tumor that typically originates from the vulvovaginal region, perineum, and pelvis in adult women. The objective of this case report and literature review is to comprehensively analyze the clinical, imaging, and pathological characteristics of atypical AAM in the female lower genital tract and pelvic floor in order to minimize preoperative misdiagnosis or missed diagnosis and ultimately optimize the clinical management strategy. The data of three cases with atypical AAM, which demonstrate similarities with other lesions observed in the female lower genital tract over the past 1.5 years, were retrospectively described. This description included clinical management, images and reports of ultrasonography (US) and magnetic resonance imaging (MRI), clinicopathological features, follow-up, and outcomes. In the Discussion section, a review of the literature on MEDLINE (PubMed) and Web of Science from the past 50 years was conducted. The three cases all underwent preoperative ultrasonography, and two of them also underwent preoperative MRI examination. Complete resection of the lesions was performed in all three cases, followed by postoperative pathological examination. The histopathology of these three cases revealed invasive angiomyxoma, as confirmed by immunohistochemical staining, which demonstrated positive expression of desmin, vimentin, estrogen, and progesterone receptors. The patients experienced a smooth postoperative recovery. Ultrasound had a diagnostic accuracy rate of 100% (3/3) for locating and determining the extent of the lesions; however, its specific diagnostic accuracy rate for identifying the pathological type was only 33% (1/3). In contrast, MRI had a diagnostic accuracy rate of 100% (2/2) for locating and determining the extent of lesions but did not show any specific diagnostic accuracy for identifying the pathological types. Our findings indicate that even if a vulvovaginal lesion presents with a superficial location, small size, limited scope, and regular shape, suspicion of atypical AAM should arise when palpation reveals toughness, tensility, and deformability under pressure. US reveals a well-defined hypoechoic to anechoic mass with uniformly distributed coarse dot echoes, with or without detectable intratumoral blood flow signal. MRI shows prolonged T1 and T2 signals with inhomogeneous enhancement and evident diffusion restriction on diffusion-weighted imaging (DWI).

Eutectogels as a Semisolid Electrolyte for Organic Electrochemical Transistors.

Organic electrochemical transistors (OECTs) are signal transducers offering high amplification, which makes them particularly advantageous for detecting weak biological signals. While OECTs typically operate with aqueous electrolytes, those employing solid-like gels as the dielectric layer can be excellent candidates for constructing wearable electrophysiology probes. Despite their potential, the impact of the gel electrolyte type and composition on the operation of the OECT and the associated device design considerations for optimal performance with a chosen electrolyte have remained ambiguous. In this work, we investigate the influence of three types of gel electrolytes-hydrogels, eutectogels, and iongels, each with varying compositions on the performance of OECTs. Our findings highlight the superiority of the eutectogel electrolyte, which comprises poly(glycerol 1,3-diglycerolate diacrylate) as the polymer matrix and choline chloride in combination with 1,3-propanediol deep eutectic solvent as the ionic component. This eutectogel electrolyte outperforms hydrogel and iongel counterparts of equivalent dimensions, yielding the most favorable transient and steady-state performance for both p-type depletion and p-type/n-type enhancement mode transistors gated with silver/silver chloride (Ag/AgCl). Furthermore, the eutectogel-integrated enhancement mode OECTs exhibit exceptional operational stability, reflected in the absence of signal-to-noise ratio (SNR) variation in the simulated electrocardiogram (ECG) recordings conducted continuously over a period of 5 h, as well as daily measurements spanning 30 days. Eutectogel-based OECTs also exhibit higher ECG signal amplitudes and SNR than their counterparts, utilizing the commercially available hydrogel, which is the most common electrolyte for cutaneous electrodes. These findings underscore the potential of eutectogels as a semisolid electrolyte for OECTs, particularly in applications demanding robust and prolonged physiological signal monitoring.

Efficient in vitro and in vivo transfection of self-amplifying mRNA with linear poly(propylenimine) and poly(ethylenimine-propylenimine) random copolymers as non-viral carriers.

Messenger RNA (mRNA) based vaccines have been introduced worldwide to combat the Covid-19 pandemic. These vaccines consist of non-amplifying mRNA formulated in lipid nanoparticles (LNPs). Consequently, LNPs are considered benchmark non-viral carriers for nucleic acid delivery. However, the formulation and manufacturing of these mRNA-LNP nanoparticles are expensive and time-consuming. Therefore, we used self-amplifying mRNA (saRNA) and synthesized novel polymers as alternative non-viral carrier platform to LNPs, which enable a simple, rapid, one-pot formulation of saRNA-polyplexes. Our novel polymer-based carrier platform consists of randomly concatenated ethylenimine and propylenimine comonomers, resulting in linear, poly(ethylenimine-ran-propylenimine) (L-PEIx-ran-PPIy) copolymers with controllable degrees of polymerization. Here we demonstrate in multiple cell lines, that our saRNA-polyplexes show comparable to higher in vitro saRNA transfection efficiencies and higher cell viabilities compared to formulations with Lipofectamine MessengerMAX™ (LFMM), a commercial, lipid-based carrier considered to be the in vitro gold standard carrier. This is especially true for our in vitro best performing saRNA-polyplexes with N/P 5, which are characterised with a size below 100 nm, a positive zeta potential, a near 100% encapsulation efficiency, a high retention capacity and the ability to protect the saRNA from degradation mediated by RNase A. Furthermore, an ex vivo hemolysis assay with pig red blood cells demonstrated that the saRNA-polyplexes exhibit negligible hemolytic activity. Finally, a bioluminescence-based in vivo study was performed over a 35-day period, and showed that the polymers result in a higher and prolonged bioluminescent signal compared to naked saRNA and L-PEI based polyplexes. Moreover, the polymers show different expression profiles compared to those of LNPs, with one of our new polymers (L-PPI250) demonstrating a higher sustained expression for at least 35 days after injection.

WSOLA for Reconstruction of Prolonged Speech Signal

WSOLA for Reconstruction of Prolonged Speech Signal

Correlation between the Coaptation and Regeneration of Tendon Stumps in Endoscopic Assisted Achilles Tendon Rupture Repair.

When the endoscopic Achilles tendon repair technique is utilized, direct stitching of the ruptured site is challenging due to the frayed tendon stumps. To explore whether undesirable coaptation of the tendon stumps influences the generation of the tendons. This study is a retrospective analysis of 46 patients who underwent a modified endoscopic Achilles tendon rupture repair from October 2018 to June 2020. Patients were divided into two groups according to the coaptation of tendon stumps on postoperative ultrasonography. Group 1 included 17 cases with undesirable coaptation (<50%), and Group 2 included 29 cases with appropriate coaptation (≥50%). Magnetic resonance imaging (MRI) was obtained postoperatively at 3, 6, and 12 months to evaluate the tendon morphological construction. Clinical evaluations were performed using the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hind foot score, the Achilles Tendon Total Rupture Score (ATRS), muscle power, and the Achilles tendon resting angle at the final follow-up. Complications were also encountered. The Student's t-test and the Mann-Whitney U-test were used to assess differences among both groups. The mean follow-up time was 37.5 ± 10.6 months in Group 1 and 39.0 ± 11.6 months in Group 2, respectively. The average age in Group 1 is slightly older than in Group 2 (37.3 ± 6.1 vs. 32.7 ± 6.3, p = 0.021). The tendon cross-section areas and thickness increased initially and decreased later on postoperative MRI evaluation. It also showed a significantly higher signal/noise quotient (SNQ) in Group 1 at postoperative 3 months. At postoperative 6 and 12 months, the SNQ between both groups was similar. The AOFAS score (95.9 ± 5.1 vs. 96.2 ± 4.9, p = 0.832), ATRS score (97.0 ± 3.6 vs. 97.7 ± 3.3, p = 0.527), and muscle power (21.38 vs. 24.74, p = 0.287) were not significantly different between both groups. However, the resting angle of Group 1 was significantly larger than that of Group 2 (4.6 ± 2.4 vs. 2.4 ± 2.3, p = 0.004). There was no difference in the complications (p = 0.628). Although complete regeneration can be finally achieved, the early stage of tendon stump regeneration can be prolonged due to undesirable coaptation when endoscopic Achilles tendon repair technique is applied. The prolonged high signal duration on MRI indicates the less-than-ideal regeneration of the tendon, which might lead to elongation of the tendon.

Statistical Validation of An Automated Method for Calculating Time Domain Heart Rate Variability on The QT Dataset.

Heart rate variability measures calculated from electrocardiography recordings reflect social competence. Clinical assessments of social skills have found that reduced heart rate variability is related to differences in the development of social skills in children and increase the risk of mental disorders. Limited by widespread manual signal processing and R-peak detection in current clinical assessments, most literature reports only short-term baseline studies, with fewer studies reporting social interaction settings with prolonged recording. There is an urgent need for an automated physiological signal processing toolbox to detect R-peaks and perform heart rate variability measurements in social settings. This paper proposes a modified automated Neurokit2 toolbox with signal processing procedures similar to the MindWare software that requires manual inspection of R-peak locations. We calculate time domain heart rate variability metrics from the publicly available QT database by PhysioNet collected at resting states and under stress tests, mimicking social interaction stress scenarios. Statistical analysis conveys that heart rate variability metrics calculation applying both signal processing approaches using the Neurokit2 toolbox are statistically equivalent in comparison to the hand-labelled R-peaks from the QT database (n= 10 in the normal sinus rhythm group, and n= 6 in the ST Change group). Such validation results are crucial for the adoption of automated toolboxes for heart rate variability measures in social interaction assessments, where more movement and mood changes of participants are expected.Clinical Relevance- This contributes to the body of evidence of the reliability of the Neurokit2 toolbox for automatic cleaning of prolonged cardiac electrophysiological signals and calculation of heart rate variability in time-domain characterization in social interaction stress assessment.

Synthesis of nucleus-satellite like Ag nanoparticles based on dielectric barrier discharge system for prolonged chemiluminescence imaging of mercury ions

Noble metal nanomaterials were unique in the field of chemiluminescence (CL) because of their high catalytic activity and surface plasmon resonance (SPR). Herein, polyhedral oligomeric silsesquioxanes modified silver nanoparticles (POSS-Ag NPs) were firstly synthesized by dielectric barrier discharge system within 40 min. Amino modified POSS (AE-POSS), as both a reducing agent and protective agent, was bonded to the surface of Ag NPs to stabilized Ag NPs through the three-dimensional framework structure to form “nucleus-satellite” like structures, which specially showed enhanced CL intensity due to increased specific surface area and SPR characteristics. Subsequently, a prolonged CL signal for over 1 h by POSS-Ag NPs - luminol system happened, which could be well observed in the CL imaging. The presence of Ag0/Ag+ and O2/·O2– charge cycling transfer on the surface of POSS-Ag NPs continuously provided large amounts of catalysts (Ag0) and CL reactants (Ag+), continuously reacting with luminol to greatly prolong the CL reaction time. Significantly, due to the mercury (Hg)-Ag alloys production in Ag NPs solution to inhibit catalytic and SPR effects, this intense and long-time CL system for the specific imaging detection of Hg2+ was developed. The detection limit of this method was 3 × 10−8 M. The enhanced prolonged CL phenomenon could improve the accuracy of chemical analysis and have promising applications in CL imaging.

Deep Learning-Aided Inertial/Visual/LiDAR Integration for GNSS-Challenging Environments.

This research develops an integrated navigation system, which fuses the measurements of the inertial measurement unit (IMU), LiDAR, and monocular camera using an extended Kalman filter (EKF) to provide accurate positioning during prolonged GNSS signal outages. The system features the use of an integrated INS/monocular visual simultaneous localization and mapping (SLAM) navigation system that takes advantage of LiDAR depth measurements to correct the scale ambiguity that results from monocular visual odometry. The proposed system was tested using two datasets, namely, the KITTI and the Leddar PixSet, which cover a wide range of driving environments. The system yielded an average reduction in the root-mean-square error (RMSE) of about 80% and 92% in the horizontal and upward directions, respectively. The proposed system was compared with an INS/monocular visual SLAM/LiDAR SLAM integration and to some state-of-the-art SLAM algorithms.

Hybrid Approach to Detect Prolonged Speech Segments

In the last 10 decades various methods have been introduced to detect prolonged speech segments automatically for stuttered speech signals. However less attention has been paid by researches in the detection of prolongation disorder at the parametric level. The aim of this study is to propose a hybrid approach to detect the prolonged speech segments by combining various spectral parameters with their recognition accuracies for the reconstructed speech signal. The paper presents prolonged segments detection by considering the parameters individually, combining various spectral parameters, validation of prolongation detection system, MFCC feature extraction process, basic model accuracies for the reconstructed signals. The proposed methods are simulated and experimented on UCLASS derived dataset. Obtained results are compared with the existing works of prolongation detection at parametric and word level. It is observed that hybrid parameters yield 92% of recognition rate for larger frame sizes of 200ms when modeled with SVM. The results are also tabulated and discussed for various metrics like sensitivity, specificity and accuracy metrics in detecting the prolonged segments. The study also focuses on the prolongation characteristics of vocalized and non-vocalized sounds at phoneme level. The detection accuracy of 71% is observed for Vocalized prolonged vowel phonemes over non-vocalized prolonged signal. Objectives: The objective of this work is to propose a hybrid algorithm to detect prolonged segments automatically for speech signal with prolongation disorder. The other objective is to evaluate the obtained spectral parameters performances by applying to various evaluation metrics and models to compute the recognition accuracy of a reconstructed signal. The objective is further extended to bring out the importance of variable frame size concept and to analyze the variations in vocalized and non-vocalized sounds. Methods: The methods adopted to detect prolonged speech segments are discussed at two levels namely at the preprocessing and modeling levels. The Preprocessing level is discussed by applying various parameters at an individual level, hybrid level by combing the Centroid, Entropy, Energy, ZCR parameters and MFCC feature extraction method. A new method has been applied using Specificity, Sensitivity and accuracy metrics to validate the prolongation detection model performance. In modeling level, the above parameters are discussed by applying evaluation metrics for the clustering and classification models like K-means, FCM and SVM. The performance of these methods is considered for evaluating and estimating the prolonged segment detection accuracy of the reconstructed speech signals of vocalized and non-vocalized sounds. All these methods are discussed in detail in the following sections. Findings: Hybridizing the spectral parameters to detect the prolonged speech segment automatically is a major finding of this work. It is also found that Specificity, sensitivity and accuracy metrics plays a major role in designing and validating the prolongation detection model. From the further experiments it is identified that the hybrid and verification metrics suits better for vocalized and non-vocalized sounds when larger frame lengths are considered. SVM has been found to perform better for all the above considerations. Novelty: As per Literature survey it is observed that individual and few parameters are applied to detect the prolongation. But works are not addressed on applying or combining more than two parameters to detect the prolonged speech segments. The novelty of this work lies in selecting and combining the spectral parameters at the preprocessing stage to detect the prolongation disorder. Spectral centroid and entropy are considered as appropriate parameters along with ZCR and Energy parameters. Hence hybridizing these parameters results in a novelty to propose an automatic prolongation detection system. Novelty is further brought by applying Specificity, sensitivity and accuracy metrics to build and evaluate the detection system for vocalized and non-vocalized prolonged sounds.

A GNSS/INS/LiDAR Integration Scheme for UAV-Based Navigation in GNSS-Challenging Environments.

Unmanned aerial vehicle (UAV) navigation has recently been the focus of many studies. The most challenging aspect of UAV navigation is maintaining accurate and reliable pose estimation. In outdoor environments, global navigation satellite systems (GNSS) are typically used for UAV localization. However, relying solely on GNSS might pose safety risks in the event of receiver malfunction or antenna installation error. In this research, an unmanned aerial system (UAS) employing the Applanix APX15 GNSS/IMU board, a Velodyne Puck LiDAR sensor, and a Sony a7R II high-resolution camera was used to collect data for the purpose of developing a multi-sensor integration system. Unfortunately, due to a malfunctioning GNSS antenna, there were numerous prolonged GNSS signal outages. As a result, the GNSS/INS processing failed after obtaining an error that exceeded 25 km. To resolve this issue and to recover the precise trajectory of the UAV, a GNSS/INS/LiDAR integrated navigation system was developed. The LiDAR data were first processed using the optimized LOAM SLAM algorithm, which yielded the position and orientation estimates. Pix4D Mapper software was then used to process the camera images in the presence of ground control points (GCPs), which resulted in the precise camera positions and orientations that served as ground truth. All sensor data were timestamped by GPS, and all datasets were sampled at 10 Hz to match those of the LiDAR scans. Two case studies were considered, namely complete GNSS outage and assistance from GNSS PPP solution. In comparison to the complete GNSS outage, the results for the second case study were significantly improved. The improvement is described in terms of RMSE reductions of approximately 51% and 78% for the horizontal and vertical directions, respectively. Additionally, the RMSE of the roll and yaw angles was reduced by 13% and 30%, respectively. However, the RMSE of the pitch angle was increased by about 13%.

Near-infrared-dye labeled tumor vascular-targeted dimer GEBP11 peptide for image-guided surgery in gastric cancer.

Positive resection margins occur in about 2.8%-8.2% gastric cancer surgeries and is associated with poor prognosis. Intraoperative guidance using Nearinfrared (NIR) fluorescence imaging is a promising technique for tumor detection and margin assessment. The goal of this study was to develop a tumor-specific probe for real-time intraoperative NIR fluorescence imaging guidance. The tumor vascular homing peptide specific for gastric cancer, GEBP11, was conjugated with a near-infrared fluorophore, Cy5.5. The binding specificity of the GEBP11 probes to tumor vascular endothelial cells were confirmed by immunofluorescent staining. The ability of the probe to detect tumor lesions was evaluated in two xenograft models. An orthotopic gastric cancer xenograft model was used to evaluate the efficacy of the GEBP11 NIR probes in real-time surgical guidance. In vitro assay suggested that both mono and dimeric GEBP11 NIR probes could bind specifically to tumor vascular epithelial cells, with dimeric peptides showed better affinity. In tumor xenograft mice, live imaging suggested that comparing with free Cy5.5 probe, significantly stronger NIR signals could be detected at the tumor site at 24-48h after injection of mono or dimeric GEBP11 probes. Dimeric GEBP11 probe showed prolonged and stronger NIR signals than mono GEBP11 probe. Biodistribution assay suggested that GEBP11 NIR probes were enriched in gastric cancer xenografts. Using dimeric GEBP11 NIR probes in real-time surgery, the tumor margins and peritoneal metastases could be clearly visualized. Histological examination confirmed the complete resection of the tumor. (GEBP11)2-ACP-Cy5.5 could be a potential useful probe for intraoperative florescence guidance in gastric cancer surgery.

The Role of Quiescence in Acute Myeloid Leukemia Growth

Acute myeloid leukemia (AML) is the most common leukemia in adults and its prognosis is usually poor. Despite the introduction of targeted treatments in recent years, AML remains a high-mortality disease with a 5-year survival of less than 30%. Emerging evidence suggest that therapy failure and leukemia relapse are due to the intra-tumoral genomic and biological heterogeneity. At biological level, AML is hierarchically organized with leukemia stem cells (LSCs) at the apex. LSCs are a rare cell sub-population with self-renewal capacity, responsible for leukemia initiation and maintenance. Standard AML therapies have limited effects on LSCs, mainly due to their property of exiting the cell cycle and enter quiescence. Preliminary data obtained in our group have shown that different leukemia-initiating oncogenes (NPMc+, PML-RARα and MLL-AF9) share the property of enforcing quiescence in pre-leukemic hematopoietic stem cells (HSCs), and that this is critical for the progression and maintenance of the leukemia clone. Underlying molecular mechanisms, however, are unknown. To this end, we have performed an in vivo reverse genetic screening to identify quiescence-related genes indispensable for leukemia growth. Among the identified hits, Socs2, Stat1 and Sytl4 silencing prevented AML outgrowth in vivo. Notably, Socs2 and Stat1 interference increased proliferation, prevented accumulation of quiescent blasts and induced apoptosis. Interestingly, Socs2 and Stat1 silencing exerted no effects on in vitro proliferation, cell cycle distribution or survival of AML blasts, suggesting that their effects are largely dependent on the in vivo leukemia context. Single-cell RNAseq (scRNAseq) analysis of Socs2-interfered blasts showed marked down-regulation of genes characterizing the dormant status of quiescent HSCs, suggesting that loss of quiescence in Socs2-interfered blasts is linked to the loss of their regenerative potential. Since dormancy and self-renewal potential in HSCs are antagonized by prolonged stress signals, we analyzed scRNAseq data for activation of the integrated stress response (ISR). Strikingly, Socs2-interfered cells showed aberrant activation of ATF4, UPR and autophagic transcriptional programs, which was evident in both proliferating and cell cycle restricted blasts, at variance with control blasts that showed increased ISR expression specifically in proliferating cells. Since elevated levels of UPR may act as danger signals and favor immune-mediated clearance in vivo, we analyzed immune-related signaling pathways. Consistently, Socs2-silenced blasts showed a dramatic down-regulation of specific immune check-point molecules, including CD24a, galectin 9 and VISTA, which are involved in the regulation of B cells, T cells, NK cells and macrophages. Based on these findings, we hypothesized that Socs2 regulates the resolution of stressful signals that eventually accumulate in hyper-proliferating AML blasts by allowing cells to enter quiescence and activate pathways of ISR resolution, including upregulation of immune check-point molecules. If blasts fail to enter quiescence, as in in the absence of Socs2 expression, cells maintain sustained ISR activation and downregulate immune check-point molecules, thus triggering immune-mediated cell death. Consistently, the anti-leukemic effect of Socs2-silencing was partially rescued upon propagation into immunocompromised mice. As well, macrophage depletion prolonged disease latency of Socs2-interfered blasts in immunocompetent mice. These findings provide preliminary evidence of the existence, in AML blasts, of an adaptive response to hyperproliferation that involves ISR activation, induction of quiescence and immune evasion. Targeting this adaptive response, as by Socs2 interference, may activate potent mechanisms of AML immune clearance.

Quantifying cerebral blood arrival times using hypoxia-mediated arterial BOLD contrast

Cerebral blood arrival and tissue transit times are sensitive measures of the efficiency of tissue perfusion and can provide clinically meaningful information on collateral blood flow status. We exploit the arterial blood oxygen level dependent (BOLD) signal contrast established by precisely decreasing, and then increasing, arterial hemoglobin saturation using respiratory re-oxygenation challenges to quantify arterial blood arrival times throughout the brain. We term this approach the Step Hemoglobin re-Oxygenation Contrast Stimulus (SHOCS). Carpet plot analysis yielded measures of signal onset (blood arrival), global transit time (gTT) and calculations of relative total blood volume. Onset times averaged across 12 healthy subjects were 1.1 ± 0.4 and 1.9 ± 0.6 for cortical gray and deep white matter, respectively. The average whole brain gTT was 4.5 ± 0.9 s. The SHOCS response was 1.7 fold higher in grey versus white matter; in line with known differences in tissue-specific blood volume fraction. SHOCS was also applied in a patient with unilateral carotid artery occlusion revealing ipsilateral prolonged signal onset with normal perfusion in the unaffected hemisphere. We anticipate that SHOCS will further inform on the extent of collateral blood flow in patients with upstream steno-occlusive vascular disease, including those already known to manifest reductions in vasodilatory reserve capacity or vascular steal.

The observed connection between the Quasi‐Biennial Oscillation and the persistence of the North Atlantic Oscillation in boreal winter

AbstractThis study reveals that the persistence of North Atlantic Oscillation (NAO) during boreal winter is closely linked to the phase of the Quasi‐Biennial Oscillation (QBO) at 30 hPa for the period 1958–2020. Our results show that the early winter (i.e., November–December) NAO signal tends to persist into the subsequent January in the easterly phase of the QBO (EQBO). However, in the westerly phase of the QBO (WQBO) there is hardly connection between the early winter and the subsequent January NAO signals. Further analysis suggests that there is stronger stratosphere–troposphere connection and stronger amplitude of the NAO during the early winters of the EQBO compared to those of the WQBO. A stronger NAO in the EQBO tends to induce enhanced positive feedback of air–sea interaction, which may contribute to a prolonged signal of the NAO. Specifically, significant surface heat flux anomalies over the high‐latitude and subtropical regions of North Atlantic induced by a stronger early winter NAO may trigger a tripolar pattern of anomalous sea surface temperature in the North Atlantic in the subsequent January. And this anomalous SST pattern may have a feedback on the atmosphere to strength the anomalous NAO by changing the atmospheric baroclinicity and synoptic eddy activities. In contrast, the NAO in the early winters of the WQBO tends to have a weaker amplitude and be confined to the troposphere. This weaker NAO is shown to induce a weaker air–sea interaction in the North Atlantic, and tends not to favour a prolonged NAO.