Current Limitations Research Articles

The Dual Roles of S-Nitrosylation of Proteins in Cancer: Molecular Mechanisms and Recent Advancements

<p class="MsoNormal" style="text-align: justify;"><span lang="EN-US" style="font-family: Nunito; color: #212529; background: white;">Protein S-nitrosylation (SNO), emerging as an important posttranslational modification, involves covalent addition of nitric oxide (NO) to the sulfur atom of cysteine in proteins. Accumulated evidence suggests that protein SNO plays crucial roles in pathophysiological mechanisms in cancer, which is attracting great attention. However, there are still controversies about whether S-nitrosylated proteins act as oncogenic proteins or tumor suppressors in cancer. In this review, we provide an overview of the early and latest evidence regarding the underlying mechanism and dual roles of SNO in cancer, in an effort to clarify its contribution in tumor progression. It has been well established that S-nitrosylated proteins restrain tumor progression in several types of cancer, while they have exhibited activities in promoting cell proliferation and inhibiting apoptosis in some other kinds of cancer. Interestingly, emerging evidence also has highlighted both its anti-cancer and pro-tumorigenic roles in several other cancer diseases. Finally, current limitations and future research prospects are presented. The overview of targeting SNO in cancer will provide new opportunities for drug development through in-depth exploration of SNO-mediated signaling pathways.</span></p>

Modeling realistic synaptic inputs of CA1 hippocampal pyramidal neurons and interneurons via Adaptive Generalized Leaky Integrate-and-Fire models

Computational models of brain regions are crucial for understanding neuronal network dynamics and the emergence of cognitive functions. However, current supercomputing limitations hinder the implementation of large networks with millions of morphological and biophysical accurate neurons. Consequently, research has focused on simplified spiking neuron models, ranging from the computationally fast Leaky Integrate and Fire (LIF) linear models to more sophisticated non-linear implementations like Adaptive Exponential (AdEX) and Izhikevic models, through Generalized Leaky Integrate and Fire (GLIF) approaches. However, in almost all cases, these models are tuned (and can be validated) only under constant current injections and they may not, in general, also reproduce experimental findings under variable currents. This study introduces an Adaptive GLIF (A-GLIF) approach that addresses this limitation by incorporating a new set of update rules. The extended A-GLIF model successfully reproduces both constant and variable current inputs, and it was validated against the results obtained using a biophysical accurate model neuron. This enhancement provides researchers with a tool to optimize spiking neuron models using classic experimental traces under constant current injections, reliably predicting responses to synaptic inputs, which can be confidently used for large-scale network implementations.

The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications.

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

Impact of Surface Composition Changes on the CO2-Reduction Performance of Au-Cu Aerogels.

Over the past decades, the electrochemical CO2-reduction reaction (CO2RR) has emerged as a promising option for facilitating intermittent energy storage while generating industrial raw materials of economic relevance such as CO. Recent studies have reported that Au-Cu bimetallic nanocatalysts feature a superior CO2-to-CO conversion as compared with the monometallic components, thus improving the noble metal utilization. Under this premise and with the added advantage of a suppressed H2-evolution reaction due to absence of a carbon support, herein, we employ bimetallic Au3Cu and AuCu aerogels (with a web thickness ≈7 nm) as CO2-reduction electrocatalysts in 0.5 M KHCO3 and compare their performance with that of a monometallic Au aerogel. We supplement this by investigating how the CO2RR-performance of these materials is affected by their surface composition, which we modified by systematically dissolving a part of their Cu-content using cyclic voltammetry (CV). To this end, the effect of this CV-driven composition change on the electrochemical surface area is quantified via Pb underpotential deposition, and the local structural and compositional changes are visually assessed by employing identical-location transmission electron microscopy and energy-dispersive X-ray analyses. When compared to the pristine aerogels, the CV-treated samples displayed superior CO Faradaic efficiencies (≈68 vs ≈92% for Au3Cu and ≈34 vs ≈87% for AuCu) and CO partial currents, with the AuCu aerogel outperforming the Au3Cu and Au counterparts in terms of Au-mass normalized CO currents among the CV-treated samples.

Improving Earth-like planet detection in radial velocity using deep learning

Many novel methods have been proposed to mitigate stellar activity for exoplanet detection as the presence of stellar activity in radial velocity (RV) measurements is the current major limitation. Unlike traditional methods that model stellar activity in the RV domain, more methods are moving in the direction of disentangling stellar activity at the spectral level. As deep neural networks have already been proven to be one of the most effective tools in data mining, in this work, we explore their potential in the context of Earth-like planet detection in RV measurements. The goal of this paper is to present a novel convolutional neural network-based algorithm that efficiently models stellar activity signals at the spectral level, enhancing the detection of Earth-like planets. Based on the idea that the presence of planets can only produce a Doppler shift at the spectral level while the presence of stellar activity can introduce a variation in the profile of spectral lines (asymmetry and depth change), we trained a convolutional neural network to build the correlation between the change in the spectral line profile and the corresponding RV, full width at half maximum (FWHM) and bisector span (BIS) values derived from the classical cross-correlation function. This algorithm has been tested on three intensively observed stars: Alpha Centauri B (HD\,128621), Tau ceti (HD\,10700), and the Sun. By injecting simulated planetary signals at the spectral level, we demonstrate that our machine learning algorithm can achieve, for HD\,128621 and HD\,10700, a detection threshold of 0.5 m/s in semi-amplitude for planets with periods ranging from 10 to 300 days. This threshold would correspond to the detection of a sim 4\,$ M oplus $ in the habitable zone of those stars. On the HARPS-N solar dataset, thanks to significantly more data, our algorithm is even more efficient at mitigating stellar activity signals and can reach a threshold of 0.2 m/s, which would correspond to a 2.2\,$ M oplus $ planet on the orbit of the Earth. To the best of our knowledge, it is the first time that such low detection thresholds are reported for the Sun, but also for other stars, and therefore this highlights the efficiency of our convolutional neural network-based algorithm at mitigating stellar activity in RV measurements.

Deepfake forensics: a survey of digital forensic methods for multimodal deepfake identification on social media

The rapid advancement of deepfake technology poses an escalating threat of misinformation and fraud enabled by manipulated media. Despite the risks, a comprehensive understanding of deepfake detection techniques has not materialized. This research tackles this knowledge gap by providing an up-to-date systematic survey of the digital forensic methods used to detect deepfakes. A rigorous methodology is followed, consolidating findings from recent publications on deepfake detection innovation. Prevalent datasets that underpin new techniques are analyzed. The effectiveness and limitations of established and emerging detection approaches across modalities including image, video, text and audio are evaluated. Insights into real-world performance are shared through case studies of high-profile deepfake incidents. Current research limitations around aspects like cross-modality detection are highlighted to inform future work. This timely survey furnishes researchers, practitioners and policymakers with a holistic overview of the state-of-the-art in deepfake detection. It concludes that continuous innovation is imperative to counter the rapidly evolving technological landscape enabling deepfakes.

Basics, benefits, and pitfalls of pupillometers assessing visual function.

Numerous commercially and non-commercially available pupillometers are nowadays able to assess various biological functions in humans, by evaluating pupils' dynamics in response to specific stimuli. However, the use of pupillometers for ophthalmic afferent evaluations (i.e., photoreceptoral responses) in real-world settings is relatively limited. Recent scientific and technological advances, coupled with artificial intelligence methods have improved the performance of such devices to objectively detect, quantify, and classify functional disturbances of the retina and the optic nerve. This review aims to summarize the scientific principles, indications, outcomes, and current limitations of pupillometry used for evaluation of afferent pathways in ophthalmic clinical settings.

Robotics in dental and facial esthetics

Dental and facial esthetics is an essential part of modern stomatology. With the development of science and technology and the advancement of interdisciplinary studies, the research of robot technology in the field of dental and facial esthetics is becoming more extensive, and its clinical applications are gradually increasing. This article provides insights into the research and application of robot technology in dental hard tissue esthetics, periodontal soft tissue esthetics, dentition space esthetics, and maxillofacial esthetics. It also highlights the current limitations and development trends and provides references for future research and application of robots in oral esthetics.

Role of Contrast in Ultrasonography: significance, types, benefits, and limitations. A comprehensive review

Contrast-enhanced ultrasonography (CEUS) has revolutionized diagnostic imaging by significantly improving the accuracy and capabilities of ultrasound technology. By utilizing contrast agents, CEUS offers enhanced visualization of blood flow, superior detection of vascular diseases, and delineation of pathological from healthy tissues. Real-time imaging capabilities afforded by CEUS have been shown to be instrumental in guiding interventions and assessing treatment efficacy, thereby contributing to personalized patient care and improved clinical outcomes. This document provides a comprehensive review of the current benefits, limitations, and future directions of contrast-enhanced ultrasonography. It acknowledges the potential for allergic reactions, the necessity for specialized training, high costs, and the occurrence of image artifacts as drawbacks, while also anticipating advancements in targeted agents and imaging techniques. Moreover, the document emphasizes the need for ongoing research to evaluate the long-term safety and efficacy of contrast agents and their impact across various medical disciplines. Despite the challenges, the integration of CEUS into clinical practice holds enormous potential to further refine diagnostic processes and enhance patient management.

From Collagen Mimetics to Collagen Hybridization and Back.

ConspectusFacilitated by the unique triple-helical protein structure, fibrous collagens, the principal proteins in animals, demonstrate a dual function of serving as building blocks for tissue scaffolds and as a bioactive material capable of swift renewal in response to environmental changes. While studies of triple-helical collagen mimetic peptides (CMPs) have been instrumental in understanding the molecular forces responsible for the folding and assembly of triple helices, as well as identifying bioactive regions of fibrous collagen molecules, single-strand CMPs that can specifically target and hybridize to denatured collagens (i.e., collagen hybridizing peptides, CHPs) have proven useful in identifying the remodeling activity of collagen-rich tissues related to development, homeostasis, and pathology. Efforts to improve the utility of CHPs have resulted in the development of new skeletal structures, such as dimeric and cyclic CHPs, as well as the incorporation of artificial amino acids, including fluorinated proline and N-substituted glycines (peptoid residues). In particular, dimeric CHPs were used to capture collagen fragments from biological fluid for biomarker study, and the introduction of peptoid-based collagen mimetics has sparked renewed interest in peptidomimetic research because peptoids enable a stable triple-helical structure and the presentation of an extensive array of side chain structures offering a versatile platform for the development of new collagen mimetics.This Account will cover the evolution of our research from CMPs as biomaterials to ongoing efforts in developing triple-helical peptides with practical theranostic potential in targeting denatured and damaged collagens. Our early efforts in functionalizing natural collagen scaffolds via noncovalent modifications led to the discovery of an entirely new use of CMPs. This discovery resulted in the development of CHPs that are now used by many different laboratories for the investigation of pathologies associated with changes in the structures of extracellular matrices including fibrosis, cancer, and mechanical damage to collagen-rich, load-bearing tissues. Here, we delve into the essential design features of CHPs contributing to their collagen binding properties and practical usage and explore the necessity for further mechanistic understanding of not only the binding processes (e.g., binding domain and stoichiometry of the hybridized complex) but also the biology of collagen degradation, from proteolytic digestion of fibrils to cellular processing of collagen fragments. We also discuss the strengths and weaknesses of peptoid-based triple-helical peptides as applied to collagen hybridization touching on thermodynamic and kinetic aspects of triple-helical folding. Finally, we highlight current limitations and future directions in the use of peptoid building blocks to develop bioactive collagen mimetics as new functional biomaterials.

Enhancing Crop Saline Stress Tolerance and Soil Remediation with Phytobeneficial Bacteria: Diverse Approaches for Improvement

Soil salinity, a pervasive issue exacerbated by factors like irrigation and climate change, poses a significant threat to global food security. The accumulation of salts not only hampers crop growth and yield but also jeopardizes the livelihoods of millions who depend on agriculture for sustenance. Elevated salt levels in saline soils induce osmotic, ionic, oxidative, and water stress in plants. Implementing biological solutions offers the most dependable and sustainable method to safeguard food security while reducing reliance on agrochemicals which hampers various physiological and metabolic processes in plants. To ensure optimal plant growth under such changing conditions, Implementing biological solutions (Rhizobacteria) offers the most dependable and sustainable method to safeguard food security while reducing reliance on agrochemicals must be integrated into agricultural practices. This chapter concisely explores the mechanisms and utilization of beneficial microorganisms in both plants and soil to mitigate salt stress. It also addresses the current limitations and suggests potential areas for improvement in future research.

Improving Micro-EDM Machining Efficiency for Titanium Alloy Fabrication with Advanced Coated Electrodes

Enhancing the operational efficacy of electrical discharge machining (EDM) is crucial for achieving optimal results in various engineering materials. This study introduces an innovative solution—the use of coated electrodes—representing a significant advancement over current limitations. The choice of coating material is critical for micro-EDM performance, necessitating a thorough investigation of its impact. This research explores the application of different coating materials (AlCrN, TiN, and Carbon) on WC electrodes in micro-EDM processes specifically designed for Ti-6Al-4V. A comprehensive assessment was conducted, focusing on key quality indicators such as depth of cut (Z), tool wear rate (TWR), overcut (OVC), and post-machining surface quality. Through rigorous experimental methods, the study demonstrates substantial improvements in these quality parameters with coated electrodes. The results show significant enhancements, including increased Z, reduced TWR and OVC, and improved surface quality. This evidence underscores the effectiveness of coated electrodes in enhancing micro-EDM performance, marking a notable advancement in the precision and quality of Ti–6Al–4V machining processes. Among the evaluated coatings, AlCrN-coated electrodes exhibited the greatest increase in Z, the most significant reduction in TWR, and the best OVC performance compared to other coatings and the uncoated counterpart.

Current Challenges of Methylation-Based Liquid Biopsies in Cancer Diagnostics

In current clinical practice, effective cancer testing and screening paradigms are limited to specific types of cancer, exhibiting varying efficiency, acceptance, and adherence. Cell-free DNA (cfDNA) methylation profiling holds promise in providing information about the presence of malignity regardless of its type and location while leveraging blood-based liquid biopsies as a method to obtain analytical samples. However, technical difficulties, costs and challenges resulting from biological variations, tumor heterogeneity, and exogenous factors persist. This method exploits the mechanisms behind cfDNA release but faces issues like fragmentation, low concentrations, and high background noise. This review explores cfDNA methylation’s origins, means of detection, and profiling for cancer diagnostics. The critical evaluation of currently available multi-cancer early detection methods (MCEDs) as well as tests targeting single genes, emphasizing their potential and limits to refine strategies for early cancer detection, are explained. The current methodology limitations, workflows, comparisons of clinically approved liquid biopsy-based methylation tests for cancer, their utilization in companion diagnostics as well as the biological limitations of the epigenetics approach are discussed, aiming to help healthcare providers as well as researchers to orient themselves in this increasingly complex and evolving field of diagnostics.

First comparison of single-tip versus single-shot pulsed field ablation for pulmonary vein isolation in paroxysmal atrial fibrillation: interim analysis of a randomized trial

Abstract Background Non-thermal pulsed field ablation (PFA) is an emerging technology to perform pulmonary vein isolation (PVI) for atrial fibrillation (AF). Different PFA systems are available, but no comparative data exist. Purpose Randomized trial to compare single-tip versus single-shot PFA for initial PVI in paroxysmal AF patients. Methods In this single-center trial, paroxysmal AF patients are prospectively enrolled and 1:1 randomized in the single-tip or single-shot PFA group. Single-tip PVI is performed using a PFA generator and a 3.5mm contact-force enabled ablation catheter guided by 3D mapping system. The pulsed electric field dosing is 25 Ampere (A) (anterior) and 22 A (posterior), respectively. In the single-shot PVI group, a 31 or 35mm pentaspline PFA catheter is used for fluoroscopy-guided PVI. Eight PFA applications (2.0 kV) are applied per PV. In this interim analysis, acute efficacy, safety and short term clinical outcome within the 3 months blanking period were assessed. A subset of patients underwent cerebral MRI to detect silent lesions. Results To date, 50 patients were enrolled and underwent PVI in conscious sedation (25 single-tip, 25 single-shot, 63 ± 5 years, 42% female, CHA2DS2-VASc 2 [1-3]). There were no differences in baseline characteristics. Acute PVI was achieved in 100%. In the single-tip group, total procedure time was significantly longer (125 ± 31 min vs. 44 ± 12 min, p <0.001) and fluoroscopy time was significantly shorter (4 ± 2 min vs. 15 ± 6 min, p <0.001) as compared to the single-shot group. One groin hematoma was noted in the single-shot group. In the single-tip group, 1 aneurysm spurium was detected and 1 pericardial tamponade requiring drainage resulted from coughing during single-tip PFA while no real-time visualization of the catheter was available. No permanent sequelae occurred. There were no PFA specific complications and no cerebral embolisms were detected in all 14 MRI scans. At 3 months, 92% (single-shot group) and 80% in the single-tip group were free from arrhythmia (p=0.42). AF recurrences in the blanking period occurred in 2 patients in the single-shot group and in 5 patients in the single-tip group after a median of 2 [1-5] days following the procedure. Conclusions In this interim analysis of a randomized trial, single-shot or single-tip PFA for PVI both demonstrated high acute efficacy and a favourable 3 months clinical outcome. Procedural time was significantly longer in the single-tip PFA group. No silent lesions were detected in cerebral MRI. Non-availability of real-time visualization and contact-force information of the single-tip ablation catheter during energy application is a current technical limitation that could be associated with complications.

Current Challenges in Pediatric Asthma

Asthma is a chronic lung disease characterized by reversible bronchoconstriction and inflammation of the bronchi. Its increasing prevalence in childhood as well as different triggers make asthma a challenging disease in several ways: defining its phenotype/endotype, the diagnostic approach (especially in younger children), therapeutic options, and systematic follow-up. Considering these problems, this review approaches the current status and limitations of guidelines used for asthma management in children. It also emphasizes the key points which could lead to a better understanding and the direction to take in future studies.

Volatile threshold switching devices for hardware security primitives: Exploiting intrinsic variability as an entropy source

In the age of the Internet of Things, the proliferation of edge devices has resulted in a significant increase in personal information that is susceptible to theft and counterfeiting at various stages of data communication. As a result, substantial attention has been focused on hardware (HW) security elements, such as the true random number generator and physical unclonable function. With the recent surge in research and development of emerging memristors, which exploit the inherent variability of these devices, there has been a notable increase in studies on HW security. Particularly, volatile threshold switch (TS) devices, which exhibit insulator/metal characteristics below/above a certain threshold voltage, show great promise as security devices due to their lower power consumption and higher cycling endurance compared to nonvolatile memory devices. Despite the promising attributes and increasing demand for TS devices for HW security, there remains a lack of a comprehensive overview covering various TS devices and their potential contributions to HW privacy. To address this gap, this review provides an encompassing analysis of different types of TS devices and their performance in HW security literature, providing insight into current limitations and the future prospects of HW security primitives based on TS devices.

Exploring Stem-Cell-Based Therapies for Retinal Regeneration

The escalating prevalence of retinal diseases—notably, age-related macular degeneration and hereditary retinal disorders—poses an intimidating challenge to ophthalmic medicine, often culminating in irreversible vision loss. Current treatments are limited and often fail to address the underlying loss of retinal cells. This paper explores the potential of stem-cell-based therapies as a promising avenue for retinal regeneration. We review the latest advancements in stem cell technology, focusing on embryonic stem cells (ESCs), pluripotent stem cells (PSCs), and mesenchymal stem cells (MSCs), and their ability to differentiate into retinal cell types. We discuss the challenges in stem cell transplantation, such as immune rejection, integration into the host retina, and functional recovery. Previous and ongoing clinical trials are examined to highlight the therapeutic efficacy and safety of these novel treatments. Additionally, we address the ethical considerations and regulatory frameworks governing stem cell research. Our analysis suggests that while stem-cell-based therapies offer a groundbreaking approach to treating retinal diseases, further research is needed to ensure long-term safety and to optimize therapeutic outcomes. This review summarizes the clinical evidence of stem cell therapy and current limitations in utilizing stem cells for retinal degeneration, such as age-related macular degeneration, retinitis pigmentosa, and Stargardt’s disease.

Three-dimensional cardiac models: a pre-clinical testing platform.

Major advancements in human pluripotent stem cell (hPSC) technology over recent years have yielded valuable tools for cardiovascular research. Multi-cell type 3-dimensional (3D) cardiac models in particular, are providing complementary approaches to animal studies that are better representatives than simple 2-dimensional (2D) cultures of differentiated hPSCs. These human 3D cardiac models can be broadly divided into two categories; namely those generated through aggregating pre-differentiated cells and those that form self-organizing structures during their in vitro differentiation from hPSCs. These models can either replicate aspects of cardiac development or enable the examination of interactions among constituent cell types, with some of these models showing increased maturity compared with 2D systems. Both groups have already emerged as physiologically relevant pre-clinical platforms for studying heart disease mechanisms, exhibiting key functional attributes of the human heart. In this review, we describe the different cardiac organoid models derived from hPSCs, their generation methods, applications in cardiovascular disease research and use in drug screening. We also address their current limitations and challenges as pre-clinical testing platforms and propose potential improvements to enhance their efficacy in cardiac drug discovery.

Direct Monitoring of Whole‐Brain Electrodynamics via High‐Spatiotemporal‐Resolution Photoacoustics with Voltage‐Sensitive Dye

AbstractBrain voltage plays a crucial role in indicating internal functions or diseases, and optical voltage imaging has gained intensive attention in recent years. Despite encouraging progress, current implementations encounter limitations pertaining to penetration depth, field of view (FOV), and photostability of indicators. To mitigate these challenges, a robust voltage‐sensitive dye (VSD)‐based whole‐field photoacoustic brain detection (WF‐PABD) platform is proposed, enabling direct evaluation of voltage dynamics across the whole brain, forming as PA‐VSD. WF‐PABD is equipped with a 512‐element ring‐array ultrasound detector capable of 360‐degree scanning, providing a large FOV (≈5 cm), high spatial resolution (≈110 µm), and rapid imaging acquisition. The proposed VSD remained ≈75% photostability after 30 min laser exposure, much greater than most calcium sensors. The optical voltage‐response mechanisms are validated and the capability of PA‐VSD to directly screen seizures is established. It is demonstrated that investigating connectivity among different brain regions allows to identify the precise location of active epileptic foci as well as the electrical conduction pathways and their directionality through fast temporal visualization. In summary, this study not only addresses the need for non‐invasive, high‐resolution, long‐term, and direct monitoring of brain voltage but also empowers exciting venues for PA applications in neuroscience.

Neuroplastic Surgery Principles of Computerized Surgical Planning in Complex Cranioplasty Reconstruction

AbstractThis article explores the evolution and implementation of three-dimensional (3D) models and Computerized Surgical Planning (CSP) for complex cranioplasty reconstruction and the advances in neuroplastic surgery principles for improved surgical outcomes. Over recent years, CSP has revolutionized the field by employing detailed medical imaging to enhance the accuracy and efficacy of 3D models and for the creation of customized cranial implants (CCIs). The study discusses the advancements of solid alloplastic implants to the future of implants with sophisticated and integrated neurotechnology to treat or enhance patient outcomes. CSP can be used to identify and mitigate complications that can occur within cranioplasty reconstruction and to create CCIs to address the postoperative challenge of temporal hollowing. Despite the promising advancements, the article acknowledges the current limitations of CSP, including cost and technological accessibility, and proposes future directions for research and development. The findings suggest that with further improvements in imaging, biomaterials, and manufacturing techniques, CSP in neuroplastic surgery and other specialties will continue to significantly enhance the precision and personalized care of cranioplasty reconstruction.