Human Subjects Research Articles

Sodium-dependent glucose co-transport proteins (SGLTs) are not involved in human glucose taste detection

The sweet taste of saccharides, such as sucrose and glucose, and other sweeteners is known to result from activation of the TAS1R2/R3 receptor expressed in taste receptor cells (TRCs) of the taste bud. Recent reports have suggested the existence of an additional sweet taste signaling pathway for metabolizable saccharides that is dependent on the activity of glucose transporters, especially SGLT1, also expressed in TRCs. We have investigated the potential contribution of SGLT1 to glucose taste signaling in humans. Concentration-response analysis of glucose mediated changes in membrane potential measured in Chinese hamster ovary (CHO) cells transiently expressing the human SGLT1 (hSGLT1) yielded an EC50 value of 452 μM. The SGLT inhibitor phlorizin inhibited the membrane potential response to 10 mM glucose with an IC50 of 3.5 μM. In contrast, EC50 values of 127 and 132 mM were obtained from concentration-response analysis of glucose taste in vehicles of water or 20 mM NaCl, respectively, by rapid throughput taste discrimination with human subjects. Lactisole, an antagonist of TAS1R2/R3, at a concentration of 1 mM completely inhibited taste responses to glucose concentrations of 250 mM and below. Phlorizin (0.2 mM) and the high potency SGLT1-selective inhibitor mizagliflozin (10 μM) failed to inhibit glucose taste detection measured at peri-threshold concentrations in the rapid throughput taste discrimination assay. A Yes/No experiment using the taste discrimination assay revealed that 0.2 mM phlorizin was discriminable from water for some subjects. Taken together the results indicate that agonist activation of TAS1R2/R3 is sufficient to account for all glucose taste without contribution by an alternative SGLT-mediated signaling pathway. Furthermore, the taste of phlorizin could be a confounding variable for studies evaluating a role for SGLTs in taste.

Emotional bargaining after litigation: An experimental study of the Coase theorem

AbstractEntitlement assignment is unimportant if transaction cost is sufficiently low, as post‐litigation bargaining can redress allocative inefficiency, or so goes the Coase theorem. Ward Farnsworth, based on interviews with lawyers, argues that animosity created during litigation, a key mechanism to (re)allocate entitlement, will hinder the conclusion of any deal following litigation. Using a laboratory experiment, we test whether animosity generated before negotiations reduce the rate at which deals are successfully concluded and find evidence for a lower deal rate under one of the treatment conditions (the raw difference being three percentage points). The small practical effect may be attributed to rationality carrying the day and/or the limited degree of animosity we can generated in the lab with human subjects. The Coase theorem holds, while Farsworth's observation should not be ignored.

Interactions between the fovea and the periphery shape misbinding of visual features in a continuous report paradigm

AbstractHuman object perception depends on the proper integration of multiple visual features, such as color and motion. When features are integrated incorrectly, they are perceptually misbound and can cause illusions. This study investigates the phenomenon of continuous misbinding of color and motion features in peripheral vision, addressing the role of spatial continuity and color configuration in binding processes. Using a novel continuous report task, human subjects reported the perceived movement direction of color-coded dots in the peripheral visual field that were either congruent or incongruent with a foveal stimulus. Results indicate that spatial continuity is crucial for feature misbinding, with a marked decrease in peripheral perceptions bound to match foveal perception when the foveal and peripheral stimuli are spatially disjointed. Additionally, performance improved significantly when peripheral and foveal features were aligned, suggesting a ‘positive illusion’ effect where congruent features enhance perceptual accuracy. This effect was independent of the color pairings used, challenging the notion that color processing discrepancies might drive erroneous perception in this stimulus. These findings highlight the complex interplay between spatial configuration and perceptual accuracy in visual feature integration, with implications for understanding the neural basis of vision and developing applications to address perceptual inaccuracies in visual disorders.

Progressive Bulbar Palsy Care: Exploring the Potential of Functional MRI for Early Detection

Progressive bulbar palsy (PBP) is a neurodegenerative disorder impacting motor neurons involved in speech, swallowing, and breathing. Early diagnosis is challenging due to limited diagnostic tools. Functional MRI (fMRI) holds promise for detecting early biomarkers and tracking disease progression, potentially improving clinical management. This study aims to explore the utility of fMRI in developing imaging biomarkers for the early detection, prognostication, and monitoring of PBP. By addressing existing gaps in the literature, the research seeks to demonstrate how fMRI can enhance diagnostic accuracy, provide predictive insights into disease progression, and improve patient outcomes. A systematic literature review was conducted using databases such as Google Scholar. The search focused on articles published from 2018 onwards, using keywords related to PBP and fMRI. Inclusion criteria included peer-reviewed studies involving human subjects relevant to the use of fMRI in PBP. Exclusion criteria excluded non-peer-reviewed articles, non-English publications, and studies not specifically addressing fMRI in PBP. Data synthesis involved both qualitative and quantitative analyses of identified biomarkers, diagnostic accuracy, and prognostic value. The review identified several fMRI biomarkers that show potential for early detection and monitoring of PBP. These biomarkers, derived from functional and structural changes in corticobulbar pathways, offer enhanced sensitivity compared to traditional diagnostic methods. Predictive models based on fMRI metrics can forecast disease progression, aiding in personalized treatment planning. The study concludes that integrating fMRI into clinical practice could lead to earlier interventions, more accurate prognostic assessments, and improved management of PBP, ultimately enhancing patient quality of life and outcomes.

CIRSE Standards of Practice on Transjugular Intrahepatic Portosystemic Shunts.

Proposed in the early 1980s as a solution for managing complications of portal hypertension, the percutaneous creation of transjugular intrahepatic portosystemic shunt has consistently gained a central role. Increasingly lower complication rates have been observed thanks to improvements in both technologies and the skills of interventional radiologists. This document is aimed at interventional radiologists and provides best practice recommendations for transjugular intrahepatic portosystemic shunt creation, describing patient selection, intraprocedural management and follow-up, in addition to recommendations in paediatric settings. The CIRSE Standards of Practice Committee established a writing group consisting of seven European clinicians with recognised expertise in the creation of transjugular intrahepatic portosystemic shunt. The writing group reviewed the existing literature performing a pragmatic evidence search using PubMed to select relevant publications in the English language and involving human subjects, preferably published from 2009 to 2024. The final recommendations were developed by consensus. TIPS creation has an established role in the successful management of portal hypertension and its complications. This Standards of Practice document provides up-to-date recommendations for patient selection, materials, its safe performance, and follow-up with complications management.

The mouse gingiva and HIF-1α, a key gene of hypoxic environment, as tools for post-mortem time estimation.

The post-mortem interval (PMI) is the time elapsed between the death of an individual and its forensic examination. It is a crucial information for judicial authorities, but current techniques still cannot establish a precise time interval. Novel approaches are therefore required. Recently, gingival tissue has emerged as interesting for forensic analysis thanks to the protection offered by lips to this tissue, limiting the influence of environmental factors. It is also easily accessible, and its sampling is minimally invasive even in the presence of rigor mortis. Moreover, the expression of HIF-1α, a master mediator of the hypoxic environment, has been described in gingival samples at different post-mortem (PM) times. We have hypothesized that the time-dependent post-mortem expression of HIF-1α could serve as a biomarker to more accurately predict the PMI. Our analyses were performed in an animal model, the mouse, where environment can be precisely controlled. Therewith, gingival tissue morphology was evaluated through histochemical staining and HIF-1α expression was analyzed by qPCR, western blots and immunofluorescence at different post-mortem times (0h to 100h). Our results showed (a) a global post-mortem stability of gingival tissue (b) a rapid increase in HIF-1α mRNA expression in the short post-mortem times followed by a slow decrease in transcript expression until 100h PM (c) an expression of the HIF- 1α protein and its degradation products, that follows the mRNA pattern (d) the presence of HIF-1α protein in the epithelial and connective layers of the tissue, with signal accumulation in both gingival strata until at least 32h post-mortem. This pilot study thus validated the mouse and the gingival tissue as models for post-mortem analyses, as well as for studying the fate of proteins such as HIF-1α. Transferring these approaches to human subjects may provide a more accurate estimate of PMI.

Application of machine learning for detecting and tracking turbulent structures in plasma fusion devices using ultra fast imaging.

This study explores the application of machine learning techniques for detecting and tracking plasma filaments around the boundary of magnetically confined tokamak plasmas. Plasma filaments, also called blobs, are responsible for enhanced turbulent transport across magnetic field lines, and their accurate characterization is crucial for optimizing the performance of magnetic fusion devices. We present a novel approach that combines machine learning methods applied to data obtained from ultra-fast cameras, including YOLO (You Only Look Once) for object detection, semantic segmentation, and specific tracking methods. This approach enables fast and accurate detection and tracking of filaments while overcoming the limitations of conventional methods, which are time-consuming and prone to human subjectivity. A significant advance in our study lies in the development of a method for automatically labeling a large batch of data, which greatly facilitates the training of supervised machine learning algorithms. Using these techniques, we obtained promising results demonstrating a significant improvement over conventional tracking methods, achieving a detection accuracy of up to 98.8%, while reducing the inference time per frame by 15% to 31% compared to conventional Kalman filter tracking. These results open up new perspectives for investigating turbulent phenomena in tokamaks, and could have important implications for the development of controlled nuclear fusion.

Thoracic Responses and Injuries of Male Post-Mortem Human Subjects in a Homogeneous Rear-Facing Seat During High-Speed Frontal Impact.

In recent post-mortem human subjects (PMHS) studies in a high-speed rear-facing frontal impact (HSRFFI), the PMHS sustained multiple rib fractures. The seatback structure and properties of the seats might contribute to these fractures. This study aimed to determine if a homogeneous rear-facing seat with foam-covered seatback would mitigate the risk of thoracic injury during an HSRFFI. Three male PMHS were subjected to the same previous HSRFFI pulse. The seating structure consisted of a homogeneous seatback composed of rigid plates with load cells and covered with both comfort and safety foam. The PMHS spine was instrumented with accelerometers and angular rate sensors. Two chestbands were attached at the level of the axilla and xiphoid, and strain gages and strain rosettes were attached to ribs. Whole-body kinematics were quantified using a motion capture system. PMHS1 and PMHS3 sustained 30 and 13 rib fractures, respectively, while PMHS2 did not sustain any fractures. Average maximum anterior-posterior (A-P) chest compressions ranged from 15.9 to 22.6%. Rib fractures occurred before and after the maximum A-P compression, so A-P chest compression alone did not correlate well with rib fracture outcomes. Thoracic inferior-superior (I-S) deformation relative to the T12 was 107.4mm for PMHS1, 27.6mm for PMHS2, and 85.1mm for PMHS3. The direction of the maximum principal strain indicated that ribs experienced shear caused by I-S chest deformation. These results will assist with the development of countermeasures to protect occupants in a rear-facing seating configuration, along with validation of human body models.

Effectiveness and Personalized Approaches in the Correction of Gummy Smile: A Systematic Review of Orthodontic and Surgical Treatments

Background/Objectives: This systematic review seeks to assess the effectiveness of different orthodontic and combined orthodontic–surgical approaches for correcting gummy smile, with a focus on treatment efficacy, duration, and the potential for integrating various techniques. The objective is to offer evidence-based recommendations for the optimal management of gummy smile. Methods: A thorough search of the literature was conducted in the PubMed, Cochrane Library, Scopus, and Web of Science databases, covering publications from 1 January 1982 to 4 November 2024. Only randomized controlled trials involving adult human subjects with available full-text articles were included, while systematic reviews, editorials, case reports, and studies involving animals or in vitro experiments were excluded. Studies were selected based on their relevance to orthodontic or combined orthodontic–surgical treatments for correcting excessive gingival display (gummy smile), particularly in cases where residual growth does not impact treatment outcomes. The primary focus was on evaluating the efficacy of these interventions in improving smile aesthetics. Follow-up data were considered when available, though not required for inclusion. Results: The findings revealed that both orthodontic and surgical methods are effective in reducing gingival display. Orthognathic surgery offers lasting outcomes, particularly for patients with vertical maxillary excess, whereas orthodontic treatments, including the use of skeletal anchorage devices, are particularly effective for less severe cases. Minimally invasive approaches, such as botulinum toxin injections, provided temporary but promising results for patients reluctant to undergo surgery. Conclusions: Orthodontic and surgical techniques are viable options for treating gummy smile, with treatment choices depending on the condition’s severity. Future research, particularly long-term randomized studies, is required to further refine treatment protocols and improve patient outcomes.

Distance and Angle Insensitive Radar-Based Multi-Human Posture Recognition Using Deep Learning

Human posture recognition has a wide range of applicability in the detective and preventive healthcare industry. Recognizing posture through frequency-modulated continuous wave (FMCW) radar poses a significant challenge as the human subject is static. Unlike existing radar-based studies, this study proposes a novel framework to extract the postures of two humans in close proximity using FMCW radar point cloud. With radar extracted range, velocity, and angle information, point clouds in the Cartesian domain are retrieved. Afterwards, unsupervised clustering is implemented to segregate the two humans, and finally a deep learning model named DenseNet is applied to classify the postures of both human subjects. Using four base postures (namely, standing, sitting on chair, sitting on floor, and lying down), ten posture combinations for two human scenarios are classified with an average accuracy of 96%. Additionally, using the centroid information of human clusters, an approach to detect and classify overlapping human participants is also introduced. Experiments with five posture combinations of two overlapping humans yielded an accuracy of above 96%. The proposed framework has the potential to offer a privacy-preserving preventive healthcare sensing platform for an elderly couple living alone.

Using High-Pass Filter to Enhance Scan Specific Learning for MRI Reconstruction without Any Extra Training Data.

In accelerated MRI, the robust artificial-neural-network for k-space interpolation (RAKI) method is an attractive learning-based reconstruction that does not require additional training data. This study was focused on obtaining high quality MR images from regular under-sampled multi-coil k-space data using a high-pass filtered RAKI (HP-RAKI) reconstruction without any extra training data. MRI scan from human subjects was under-sampled with a regular pattern using skipped phase encoding and a fully sampled k-space center. A high-pass (HP) filter was applied in k-space to reduce image support to facilitate linear prediction. The HP filtered k-space center was used to train the RAKI network without any extra training data. The unacquired k-space data can be predicted from a trained RAKI network with optimized parameters. Final reconstruction was obtained after performing an inverse HP filtering for the predicted k-space data. This HP-RAKI method can be extended to corresponding residual structure (HP-rRAKI). HP-RAKI was compared with GRAPPA, HP-GRAPPA, RAKI and MW-RAKI algorithms, and HP-rRAKI was compared with corresponding residual extensions, including rRAKI and MW-rRAKI, all qualitatively and quantitatively using visual inspection and such metrics as SSIM and PSNR. HP-RAKI and HP-rRAKI were found to be effective in reconstructing MR images even at high acceleration factors. HP-RAKI and HP-rRAKI compared favorably with other algorithms. Using high-pass filtered central k-space data for training, HP-RAKI offers higher reconstruction quality for regularly under-sampled multi-coil k-space data without any extra training data. It has shown promising capabilities for fast MRI applications, especially those lacking fully sampled training data.

Aperiodic (1/f) neural activity robustly tracks symptom severity changes in treatment-resistant depression.

A reliable physiological biomarker for Major Depressive Disorder is essential for developing and optimizing neuromodulatory treatment paradigms. This study investigates a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours. We analyze brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human subjects (nfemale= 3, nmale = 2). This surgical setting allows for precise temporal and spatial sensitivity in the ventromedial prefrontal cortex, a challenging area to measure. We focused on the aperiodic slope of the power spectral density, a metric reflecting the balance of activity across all frequency bands and serving as a proxy for excitatory/inhibitory balance in the brain. Our findings demonstrate that shifts in aperiodic slope correlate with depression severity, with flatter (less negative) slopes indicating reduced depression severity. This significant correlation was observed in all N=5 subjects, particularly in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient responses to Major Depressive Disorder treatment, paving the way for individualized therapies in both intracranial and non-invasive monitoring contexts.

Adipocyte Apoptosis Following a Novel Method for Double Chin Reduction: A Pilot Human Histology Study.

Submental fullness is perceived as unattractive by both men and women. The noninvasive simultaneous delivery of HIFES and synchronized radiofrequency+ (Sync RF+) technologies aims to address the submental fullness by concurrently targeting the skin, adipose tissue, and weakened anterior belly of the digastric muscle, the three contributing layers to the double chin appearance. This study aims to investigate the histological changes to adipose tissue related to cell morphology, caspase-7, and Bcl-2 levels to detect adipocyte apoptosis following the HIFES and Sync RF+ treatment on human subjects. The active group (n = 6) received single 20-min treatment on the submental area, while the control group (n = 2) did not receive any treatment. Biopsies of subcutaneous fat tissue were obtained at baseline, and 24 h and 7 days posttreatment. The specimens were histologically and immunohistochemically analyzed for changes in morphology, caspase-7, and Bcl-2 levels. Observed caspase-7 levels increased by 511% at 24-h posttreatment, and 101% at 7 days (p < 0.0001), while the Bcl-2 levels decreased by 89% at 24 h and 24% at 7 days posttreatment (p < 0.0001). The control group had no statistically significant relative changes in the activity of caspase-7. Posttreatment adipocytes were shrunken in size, and shapes lost their uniformity compared to baseline. Five of six subjects reported the treatment as being comfortable. No adverse events were observed during the study. The results of this human histology study indicate that noninvasive HIFES and Sync RF+ technologies have a favorable safety profile for submental fat reduction through the induction of adipocyte apoptosis. ClinicalTrials.gov identifier: NCT06282172.

Mass layoffs at BYJU’S – founder’s dilemma

Learning outcomes This case study provides students/managers an opportunity to learn about the following: to infer the challenges involved in the downsizing of employees; to asses and evaluate BYJU’S organizational culture; and to determine the impact of workplace toxicity. Case overview/synopsis The focus of this case is the controversy faced by BYJU’S due to its mass layoffs and toxic work culture. This case discusses the CEO’s dilemma in resolving the controversy. Two rounds of mass layoffs at BYJU’S are discussed in detail. The industrial dispute filed by Employees Union against BYJU’S accusing it of denying due compensation to laid-off employees is also discussed. This case consists of a section explaining the toxic work culture at BYJU’S, which is supported by employee complaints. The CEO’s justification and apology have been illustrated in this case. The case ends with a closing dilemma and challenges faced by the CEO. Complexity academic level The case is best suited for undergraduate students studying Human Resources Management subjects in Commerce and Business Management streams. The authors suggest that the instructor inform students to read the case before attending the 90-min session. It can be executed in the classroom after discussing the theoretical concepts. Supplementary material Teaching notes are available for educators only. Subject code CSS 6: Human Resource Management.

Brain functional connectivity under teleoperation latency: a fNIRS study

IntroductionLong-distance robot teleoperation faces high latencies that pose cognitive challenges to human operators. Latency between command, execution, and feedback in teleoperation can impair performance and affect operators’ mental state. The neural underpinnings of these effects are not well understood.MethodsThis study aims to understand the cognitive impact of latency in teleoperation and the related mitigation methods, using functional Near-Infrared Spectroscopy (fNIRS) to analyze functional connectivity. A human subject experiment (n = 41) of a simulated remote robot manipulation task was performed. Three conditions were tested: no latency, with visual and haptic latency, with visual latency and no haptic latency. fNIRS and performance data were recorded and analyzed.ResultsThe presence of latency in teleoperation significantly increased functional connectivity within and between prefrontal and motor cortexes. Maintaining visual latency while providing real-time haptic feedback reduced the average functional connectivity in all cortical networks and showed a significantly different connectivity ratio within prefrontal and motor cortical networks. The performance results showed the worst performance in the all-delayed condition and best performance in no latency condition, which echoes the neural activity patterns.ConclusionThe study provides neurological evidence that latency in teleoperation increases cognitive load, anxiety, and challenges in motion planning and control. Real-time haptic feedback, however, positively influences neural pathways related to cognition, decision-making, and sensorimotor processes. This research can inform the design of ergonomic teleoperation systems that mitigate the effects of latency.

CLINICAL EFFECTIVENESS AND FEATURES OF THE POSTOPERATIVE PERIOD IN PATIENTS AFTER OSTEOSYNTHESIS OF THE MANDIBLE USING CELL TECHNOLOGIES

Due to a signifi cant increase in the frequency and complexity of maxillofacial injuries, one of the priorities in the development of modern surgical dentistry is the search for new eff ective methods of treating facial bone fractures. In recent decades, the attention of clinicians has been focused on biological treatment methods aimed at restoring bone defects using cell technologies and biological transplants.The aim of the study was to determine the eff ect of using osteoplastic materials based on multipotent adipose- derived mesenchymal stromal cells in dental patients in the surgical treatment of mandibular fractures.Materials and methods. The clinical material included 56 patients, 13 of whom underwent mandibular osteosynthesis with hydroxyapatite bone graft substitute (subgroup 1I), 25 of whom underwent surgery with a combination of multipotent adipose tissue mesenchymal stromal cells, hydroxyapatite bone graft substitute and platelet-rich plasma (subgroup 1B), and 18 of whom underwent spontaneous healing of the fracture line (subgroup 1C). Patients were clinically evaluated on a daily basis. Clinical parameters were assessed on days 1, 3, 5, 7, 10, 14 and 28 after surgery. The postoperative pain syndrome was assessed using the Numerical Rating Scale (NRS), considering the subjective signs of pain in the operated patients.The statistical processing of the study results was performed using the statistical analysis software for biomedical research ‘Microsoft Excel 21’ and ‘Statistica’ (licence number STA862D175437Q). In the statistical processing of the results, we used the variational analysis of series – calculation of the arithmetic mean and its standard error (Mim) – and assessed the signifi cance of diff erences in the results obtained in the comparison groups using the Student’s t-test method. p&lt;0.05 was considered a signifi cant diff erence. [17]. The study was conducted in accordance with the basic provisions of the «Rules of Ethical Principles for Scientifi c Medical Research Involving Human Subjects» approved by the Declaration of Helsinki (1964-2013), ICH GCP (1996), EEC Directive 609 (24.11.1986), Orders of the Ministry of Health of Ukraine ¹ 690 of 23.09.2009, ¹ 944 of 14.12.2009, ¹ 616 of 03.08.2012. The Commission on Biomedical Ethics of the Bukovinian State Medical University found no violations of ethical and moral standards in the conduct of the research (ProtocolNo. 6, 16.03.2023). Patients signed informed consent to participate in this study and all measures were taken to ensure their anonymity.The results. The comparative analysis of the clinical eff ectiveness of the use of various osteoplastic materials in the performance of osteosynthesis surgery of the lower law confi rmed the advantages of the use of bone tissue substitute based on hydroxyapatite and its combination with multipotent adipose tissue mesenchymal stromal cells before spontaneous augmentation. It is confi rmed by the data of subjective and objective symptoms of patients during the postoperative period.Conclusions. Our data show that osteoplastic material based on multipotent mesenchymal stromal cells of adipose tissue, bone substitute based on hydroxyapatite and platelet-rich blood plasma is a promising biological material. Its application improves the regenerative and reparative properties of bone tissue, facilitates the postoperative period and shortens the duration of hospitalization, promotes the development of innovative ways of reconstructive osteogenesis in modern maxillofacial surgery.

Identification and functional validation of variants in the promoter region of HAND1 gene in sporadic tetralogy of Fallot.

Tetralogy of Fallot (TOF) is a common congenital heart disease (CHD) but the impact of the variants of the HAND1 gene promoter region has not been explored. DNA from blood samples of 612 subjects (300 sporadic TOF patients and 312 healthy controls) was sequenced to identify variants in the HAND1 gene promoter region that were further tested by cellular function experiments including dual-luciferase reporter gene assays, electrophoretic mobility shift analysis (EMSA), and bioinformatics analysis using JASPAR, a transcription factor binding site database. Eight variants in HAND1 gene promoter region were identified with 3 only found in TOF patients including one novel g.3639 G > T. All 3 variants significantly reduced the transcriptional activity of HAND1 gene promoter in an in vitro reporter assay (p < 0.05). JASPAR analysis indicated that these variants may alter the binding sites of transcription factors, potentially associated with TOF formation. In the promoter region of HAND1gene of TOF patients, 3 variants were found only in the patients including one found for the first time. These variants decreased transcription factor activity. Therefore, the present study implies the role of HAND1 gene in the pathogenesis of TOF and further provides new insights into the genetic basis of TOF formation. Sequencing of DNA from 612 human subjects (300 TOF patients and 312 healthy controls) identified 8 variants in the promoter region of HAND1 gene with 3 found only in TOF including 1 newly identified. Reduced transcriptional activity at these 3 variants was confirmed by dual-luciferase reporter gene assay and EMSA assay. Predictions from the JASPAR database suggest altered binding sites of transcription factors by the variants. We for the first time demonstrate variants in the HAND1 promoter and that cause cellular dysfunction. The variants identified may have a pathological role in the formation of TOF.

Abstract 4125419: Very-Low-Density Lipoprotein Induces Neuronal Growth with Increased Tyrosine Hydroxylase Expression through Cardiomyocyte-Secreted Exosomes in Metabolic Syndrome

Introduction: Metabolic syndrome (MS) is an important predisposing factor for atrial fibrillation, and is highly related to the autonomic nervous system. Triglyceride-rich very-low-density lipoprotein (VLDL) has specific VLDL receptors (VLDLR), which are abundantly expressed in cardiomyocytes. Hypothesis: VLDL affects neuronal growth through cardiomyocyte-secreted exosomes in metabolic syndrome. Goals/Aims: To determine whether exosomes from VLDL-incubated cardiomyocytes can alter neuronal proliferation. Methods/ Approach: HL-1 cardiomyocytes were incubated with VLDL isolated from human subjects with MS, and exosomes were extracted at the end of the incubation period. VLDLR knockdown HL-1 cells were used to determine the role of VLDLR in exosome secretion. The molecular contents of exosomes were determined by mass spectrometry, which identified neurotropic proteins only detected in the exosomes of MS VLDL-incubated cardiomyocytes. We selected transmembrane protein 14B (TMEM14B) to investigate its effect on neuronal proliferation in P19 cells. Results: Regardless of the knockdown or overexpression of VLDLR in HL-1 cardiomyocytes, exosomes isolated from after VLDL incubation were shown to cause 2.062-fold and 2.084-fold expression of tyrosine hydroxylase (TH) in P19 cells, relative to P19 cells induced by non-VLDL-treated HL-1 cardiomyocyte-secreted exosomes. A similar trend could be seen with HL-1 cardiomyocytes without VLDLR editing, as VLDL-incubated HL-1 cardiomyocytes produced exosomes that could cause 1.926-fold increase in P19 TH expression, relative to treatment by exosomes from HL-1 cardiomyocytes without VLDL-incubation. The P19 cells incubated with TMEM14B demonstrated increased neurite length, with an average of 2.342-fold neurite length when compared with that of control cells. Conclusions: VLDL in MS induced HL-1 cardiomyocytes to secrete exosomes containing neurotrophic molecules and increased dendritic growth of neuronal cells. This effect was VLDLR-independent and was partially caused by TMEM14B in the exosomes.

Loureirin B Accelerates Diabetic Wound Healing by Promoting TGFβ/Smad-Dependent Macrophage M2 Polarization: A Concerted Analytical Approach Through Single-Cell RNA Sequencing and Experimental Verification.

Diabetic wound (DW) represent a significant clinical challenge and often fail to heal effectively. Loureirin B (LB), a flavonoid extracted from dragon's blood, has shown potential by influencing macrophage polarization and promoting wound healing. However, its mechanisms and efficacy in DW remain to be explored. This study employed single-cell RNA sequencing to analyze the classification of cells in diabetic foot ulcers and to identify the related mechanisms influenced by macrophages. Molecular docking was used to predict the interactions of LB with key proteins in the TGFβ/Smad signaling pathway. The effects of LB on macrophage polarization and wound healing were further validated through invitro and invivo experiments using a DW model. Single-cell analysis identified specific macrophage subtypes involved in the DW healing process and highlighted the role of the TGFβ/Smad pathway. Molecular docking suggested the potential action within the TGFβ/Smad pathway. Invitro studies showed that under high glucose conditions, LB promoted macrophage polarization from pro-inflammatory M1 to healing-promoting M2 and ECM production in fibroblasts by activating TGF-β/Smad signaling. Invivo, LB treatment enhanced wound healing rates in diabetic mice and promoted macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling. LB regulates macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling to promote DW healing. These findings suggest that LB could be a potential therapeutic agent for improving DW healing, emphasizing the need for further clinical studies to explore its efficacy and mechanisms in human subjects.

Causal inference predicts the transition from integration to segmentation in motion perception.

Motion provides a powerful sensory cue for segmenting a visual scene into objects and inferring the causal relationships between objects. Fundamental mechanisms involved in this process are the integration and segmentation of local motion signals. However, the computations that govern whether local motion signals are perceptually integrated or segmented remain unclear. Hierarchical Bayesian causal inference has recently been proposed as a model for these computations, yet a hallmark prediction of the model - its dependency on sensory uncertainty - has remained untested. We used a recently developed hierarchical stimulus configuration to measure how human subjects integrate or segment local motion signals while manipulating motion coherence to control sensory uncertainty. We found that (a) the perceptual transition from motion integration to segmentation shifts with sensory uncertainty, and (b) that perceptual variability is maximal around this transition point. Both findings were predicted by the model and challenge conventional interpretations of motion repulsion effects.