Alternative Signal Research Articles

Correlation between proprioception, functionality, patient-reported knee condition and joint acoustic emissions.

Non-invasive assessment of joint status using acoustic emissions (AE) is a growing research area that has the potential to translate into clinical practice. The purpose of this study is to investigate the correlation of the knee's AE with measures of proprioception, self-assessment, and performance, as it can be hypothesised that, AE parameters will correlate with joint function metrics due to AE being recorded during interaction of the articular surfaces. Threshold to detect passive motion (TTDPM), Knee Osteoarthritis Outcome Scores (KOOS) and 5 times sit-to-stand test (5STS) were collected from 51 participant. Knee AE were recorded during cycling with 30 and 60 rpm cadences using two sensors in different frequency ranges and three modes of AE event detection. Weak (0.297, p = 0.048) to moderate (0.475, p = 0.001) Spearman's correlations were observed between longer 5STS time and AE parameters (i.e. higher median absolute energy, signal strength, longer AE event rise time and duration). Similarly, AE parameters shown correlation with lower KOOS, especially in the "Function in Sports and Recreation" and "Activities of Daily Living" subscales with correlation coefficients for higher median amplitude up to 0.441, p = 0.001 and 0.403, p = 0.004, respectively. The correlation with the TTDPM was not detected for most of the AE parameters. Additionally, a lower frequency sensor and 60 rpm cadence AE recordings showed higher correlations. Considering that this study included subjects from the general population and the number of participants with KOOS <70 was relatively small, higher correlations might be expected for clinically confirmed OA cases. Additionally, different ICCs might be expected for alternative signal parameters and proprioception assessment methods. Overall, the study confirms that AE monitoring offers an additional modality of joint assessment that reflects interaction between cartilage surfaces and can complement orthopaedic diagnostics, especially in the context of remote monitoring, drug testing, and rehabilitation.

Evaluation of the Multidimensional Enhanced Lateral Flow Immunoassay in Point-of-Care Nanosensors.

Point-of-care (POC) nanosensors with high screening efficiency show promise for user-friendly manipulation in the ever-increasing on-site analysis demand for illness diagnosis, environmental monitoring, and food safety. Currently, inspired by the merits of integrating advanced nanomaterials, molecular biology, machine learning, and artificial intelligence, lateral flow immunoassay (LFIA)-based POC nanosensors have been devoted to satisfying the commercial demands in terms of sensitivity, specificity, and practicality. Herein, we examine the use of multidimensional enhanced LFIA in various fields over the past two decades, focusing on introducing advanced nanomaterials to improve the acquisition capability of small order of magnitude targets through engineering transformations and emphasizing interdomain fusion to collaboratively address the inherent challenges in current commercial applications, such as multiplexing, development of detectors for quantitative analysis, more practical on-site monitoring, and sensitivity enhancement. Specifically, this comprehensive review encompasses the latest advances in comprehending LFIA with an alternative signal transduction pattern, aiming to achieve rapid, ultrasensitive, and "sample-to-answer" available options with progressive applications for POC nanosensors. In summary, through the cross-collaboration development of disciplines, LFIA has the potential to break the barriers toward commercialization and achieve laboratory-level POC nanosensors, thus leading to the emergence of the next generation of LFIA.

The Role of eHMI in Reducing Driver Overtaking Decisions Around Low-speed Automated Vehicles Yielding to Pedestrians

As low speed automated vehicles (LSAVs) are further introduced into our driving fleet, driver-LSAV interactions may put pedestrians and other vulnerable road users at risk, as drivers could be confused by LSAVs and respond inappropriately when a pedestrian is present. A total of 242 participants with a driver’s license participated in an online survey to assess the ambiguity of the external human-machine interface (eHMI) or signaling system used by a recently deployed LSAV. Participants were shown signaling conditions presented as animated GIFs and were told to imagine they were following the LSAV as it stopped and turned on the signal. Participants were more likely to indicate that they would overtake the MCM when presented with the flashing hazards eHMI while the MCM was turning right compared to the alternative signal conditions. Correct shuttle behavior interpretation was found to be an important influence in participants’ choice in overtaking or waiting behaviors.

In Silico Analysis and Development of the Secretory Expression of D-Psicose-3-Epimerase in Escherichia coli.

D-psicose-3-epimerase (DPEase), a key enzyme for D-psicose production, has been successfully expressed in Escherichia coli with high yield. However, intracellular expression results in high downstream processing costs and greater risk of lipopolysaccharide (LPS) contamination during cell disruption. The secretory expression of DPEase could minimize the number of purification steps and prevent LPS contamination, but achieving the secretion expression of DPEase in E. coli is challenging and has not been reported due to certain limitations. This study addresses these challenges by enhancing the secretion of DPEase in E. coli through computational predictions and structural analyses. Signal peptide prediction identified PelB as the most effective signal peptide for DPEase localization and enhanced solubility. Supplementary strategies included the addition of 0.1% (v/v) Triton X-100 to promote protein secretion, resulting in higher extracellular DPEase (0.5 unit/mL). Low-temperature expression (20 °C) mitigated the formation of inclusion bodies, thus enhancing DPEase solubility. Our findings highlight the pivotal role of signal peptide selection in modulating DPEase solubility and activity, offering valuable insights for protein expression and secretion studies, especially for rare sugar production. Ongoing exploration of alternative signal peptides and refinement of secretion strategies promise further enhancement in enzyme secretion efficiency and process safety, paving the way for broader applications in biotechnology.

Growth‐Induced Extinction Development of Gold Nanoclusters as Signal Transducers for Quantitative Immunoassays

AbstractSignal transducers are crucial in bioassay platforms for converting target detection into recordable signals. Commonly used color development for immunoassays involves enzymes and colorimetric substrates. However, due to cost and environmental issues, practical point‐of‐care testing requires alternative signal transducers. Growth‐induced extinction (absorption and scattering) of gold nanoclusters (AuNCs) is proposed as a novel approach for quantitative immunoassays. AuNCs devoid of localized surface plasmon resonance (LSPR) are used as seeds for growth reactions. Through reactions with a growth solution comprised of gold precursor and mild reductant, AuNCs of varying concentrations underwent controlled growth, resulting in nanoparticles of different sizes exhibiting distinct LSPR‐mediated extinction bands. Notably, the seed concentration exhibited a robust correlation with the resulting extinction of the grown particles on a small scale of 110 µL for a 96‐well microplate platform. To demonstrate this signal transduction mechanism, immunosorbent assays are performed using the conjugates of AuNC and detection antibody. The sandwich‐type assay successfully quantified a model antigen, human immunoglobulin G (hIgG), by monitoring LSPR wavelength and absorbance. This assay demonstrated a working range of 0.001–1 µg mL−1 and limit of detection of 1.19 ng mL−1. Signal transducers using the growth of AuNCs offer new alternative candidates for immunoassay platforms.

Plasticity and lineage commitment of individual TH1 cells are determined by stable T-bet expression quantities.

T helper 1 (TH1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated TH1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the TH2 lineage: T-bet quantities were inversely correlated with the ability to express the TH2 lineage-specifying transcription factor GATA-3 and TH2 cytokines. Reprogramed TH1 cells acquired graded mixed TH1 + TH2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated TH1 cells was essential to ensure TH1 cell stability. Thus, innate cytokine signals regulate TH1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.

Premarital Counseling on the Alpha Thalassemia Allele HBA2:c.*94A&gt;G

The mutation HBA2:c.*94A&gt;G (AATAAA&gt;AATAAG; rs63751269) is a 3′-UTR (3 prime untranslated region) single-nucleotide substitution in the polyadenylation (PA) signal of HBA2 (αPA:A→G). This pathogenic (CADD score, 14.92) variant is sporadic in the Arabian Peninsula. It results in inefficient mRNA processing, transcription termination, and possibly using an alternate cryptic downstream polyadenylation signal. As a result, the allele αT (or αT-Saudi) poses challenges in premarital counseling with respect to fetal risk of hemoglobin H disease. Homozygous HBA2:c.*94A&gt;G (αTα/αTα) results in moderate-to-severe microcytosis (mean red cell volume, MCV, 55 to 65 fL), reflecting markedly impaired hemoglobin synthesis (hemoglobin H disease). Homozygous rightward -α3.7 (a 3804-neocleotide deletion allele, NM_000517.4:c.[-2_-3delAC; −α3.7]), on the other hand, results in mild microcytosis (MCV, 70 to 75 fL, alpha-thalassemia trait). Thus, HBA2:c.*94A&gt;G is more damaging than -α3.7. Consistently, the value of MCV in compound heterozygosity, HBA2:c.*94A&gt;G and −α3.7, is 65 to 70 fL. We report here a healthy couple who presented for premarital counseling on their hemoglobinopathy. The man has homozygous HBA2:c.*94A&gt;G (αTα/αTα), and the woman has compound heterozygous (−α3.7/αTα, also annotated as: −3.7α/αTα). As a result, the genotype of their offspring would be that of the father (αTα/αTα) or the mother (−α3.7/αTα). The counseling was mainly based on the benign phenotypes of the parents. As both were asymptomatic and their anemia was clinically insignificant, they proceeded with the marriage.

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells

BackgroundThe ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro.MethodsUsing two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile.ResultsSignificant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation.ConclusionsBased on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.

Grades and Employer Learning

This study examines the labor-market returns of skill signals. We identify the labor-market effect of grade point averages (GPA) by leveraging a nationwide change in the scaling of grades in Danish universities. Results show that a reform-induced increase in GPA that is unrelated to ability causes higher earnings immediately after graduation, but the effect fades in subsequent years. The effect at labor-market entry is largest for individuals with fewer alternative signals and the earnings adjustment occurs both within and across firms. Although employers initially screen candidates based on skill signals, our findings suggest that they rapidly learn about worker productivity.

Unraveling the Corrosion of the Ti–6Al–4V Orthopedic Alloy in Phosphate-Buffered Saline (PBS) Solution: Influence of Frequency and Potential

This paper addresses the interplay between electrical fields in the human body and the corrosion behavior of Ti-6Al-4V alloy, a prevalent orthopedic material. The study investigates the impact of alternative electrical signals at different frequencies on the alloy’s electrochemical behavior in a simulated body environment. The human body always has natural sinusoidal potential due to, e.g., heart palpitations and brain/nervous system activities. Ignoring such natural activities may lead to underestimating the corrosion performance of the Ti-6Al-4V alloy in the body. By analyzing anodic and cathodic responses and the net faradaic current induced by alternating current potential, the research sheds light on the influence of electrical fields on corrosion rates. Understanding these dynamics could lead to improved implant materials, mitigating corrosion-related challenges and enhancing implant performance over the long term. Results of this work indicated that frequent oxidation and reduction at certain frequencies may induce corrosion and hinder biomimetic apatite formation, impacting osseointegration. Natural alternative currents in the body affect the corrosion performance of Ti-based implant alloys, highlighting the need for consideration in biomedical applications.

Mathematical Representation for speech signal based on ‎polynomial equation

The sound is an important vital information that it relies to recognize the character when lessening to it. Therefore, the audio signal adopted into many important applications. Sound forming and synthesizing in addition to distinguishing the speaker are so important in fields of digital signal processing. In this paper, work is done to represent acquired acoustic signal based on mathematical techniques. Mathematical representation provides deal with the sound signal which lead to smoothing, amplification or compression, in addition to the sound filtering process. In the proposed algorithm, polynomials of various degrees were adopted as a mathematical representation for speech signal, then the retrieved speech was studied based on level of clarity and the possibility of adopting it as an alternative signal in terms of the proximity to the original sound and the amount of noise added to it. The results shows that the proposed algorithm with degree of polynomial 20 and segment length 25 had the best sound representation and so closed to the original, which clearly seen from the evaluation parameters (Correlation=0.9993, Mean squared error(MSE) =1.32e-06, Standard deviation(STD)=1.80e-05 and the Euclidean dimension(ED) =0.1703).

JAML promotes the antitumor role of tumor-resident CD8+ T cells by facilitating their innate-like function in human lung cancer

Tissue-resident memory CD8+T cells (CD8+TRMs) are thought to play a crucial role in cancer immunosurveillance. However, the characteristics of CD8+TRMs in the tumor microenvironment (TME) of human non-small cell lung cancer (NSCLC) remain unclear. Here, we report that CD8+TRMs accumulate explicitly and exhibit a unique gene expression profile in the TME of NSCLC. Interestingly, these tumor-associated CD8+TRMs uniquely exhibit an innate-like phenotype. Importantly, we found that junction adhesion molecule-like (JAML) provides an alternative costimulatory signal to activate tumor-associated CD8+TRMs via combination with cancer cell-derived CXADR (CXADR Ig-like cell adhesion molecule). Furthermore, we demonstrated that activating JAML could promote the expression of TLR1/2 on CD8+TRMs, inhibit tumor progression and prolong the survival of tumor-bearing mice. Finally, we found that higher CD8+TRMs and JAML expression in the TME could predict favorable clinical outcomes in NSCLC patients. Our study reveals an intrinsic bias of CD8+TRMs for receiving the tumor-derived costimulatory signal in the TME, which sustains their innate-like function and antitumor role. These findings will shed more light on the biology of CD8+TRMs and aid in the development of potential targeted treatment strategies for NSCLC.

Highly sensitive and reversible MXene-based micro quartz tuning fork gas sensors with tunable selectivity

Due to their distinctive morphology, significant surface-to-volume ratio, and metal-like electrical conductivity, MXenes have emerged as highly promising gas-sensing materials. Traditional MXene-based gas sensors predominantly rely on the electrical conductivity of MXenes for signal transduction. However, it is crucial to explore alternative signal transduction mechanisms to fully unlock the potential of MXenes in gas sensing applications. In this study, we have successfully showcased the development of a mass-transduction-based MXene gas sensor, utilizing MXenes as the adaptable receptor and MQTF as the transducer. The interaction between the gas analyte and MXenes induces a change in mass, resulting in a resonant frequency shift of the MQTF. This signal transduction mechanism eliminates the dependency on the electrical conductivity of MXenes, offering a broader range of possibilities for chemical modification of MXenes without concerns about compromising their conductivity. By engineering Ti3C2Tx surfaces, we have demonstrated high sensitivity and selectivity tuning of MXene-MQTF gas sensors for detecting CO, SO2, and NH3. This antisymmetric mass-transduction-based (low-cost, stable, sensitive, and practical tuning fork-based) MXene gas sensor demonstrated exceptional sensing performance, customizable selectivity, and high cost-effectiveness. This study paves the way for designing high-performance MXene-based chemical sensors and expands the scope of potential applications in air quality monitoring, wearable devices, the Internet of Things (IoT), and robotics.

Open knowledge disclosure and firm value: a signalling theory perspective

ABSTRACT A growing number of firms are openly disclosing knowledge through academic journals and conferences; however, the impact of this practice on their market value needs further research. From a signalling theory perspective, we investigate the relationship between open knowledge disclosure and firm value and identify potential contingency factors. We propose that open knowledge disclosure conveys a firm’s technical capability and commitment to open science, consequently contributing to its market value. Drawing upon data from listed companies within China’s information and communication technology sector, we confirm that open knowledge disclosure enhances firm value. Furthermore, this enhancement is more pronounced for small firms, young firms, private firms, firms with few patents, firms drafting few technical standards, or firms operating in an immature technology market. Our findings suggest that firms, especially those facing high information asymmetry or lacking alternative signals, can increase their market value by sending positive signals through open knowledge disclosure.

Assessment of the impact of direct in vitro PFAS treatment on mouse spermatozoa.

Poly- and per-fluoroalkyl substances (PFAS) are synthetic environmentally persistent chemicals. Despite the phaseout of specific PFAS, their inherent stability has resulted in ubiquitous and enduring environmental contamination. PFAS bioaccumulation has been reported globally with omnipresence in most populations wherein they have been associated with a range of negative health effects, including strong associations with increased instances of testicular cancer and reductions in overall semen quality. To elucidate the biological basis of such effects, we employed an acute in vitro exposure model in which the spermatozoa of adult male mice were exposed to a cocktail of PFAS chemicals at environmentally relevant concentrations. We hypothesized that direct PFAS treatment of spermatozoa would induce reactive oxygen species generation and compromise the functional profile and DNA integrity of exposed cells. Despite this, post-exposure functional testing revealed that short-term PFAS exposure (3 h) did not elicit a cytotoxic effect, nor did it overtly influence the functional profile, capacitation rate, or the in vitro fertilization ability of spermatozoa. PFAS treatment of spermatozoa did, however, result in a significant delay in the developmental progression of the day 4 pre-implantation embryos produced in vitro. This developmental delay could not be attributed to a loss of sperm DNA integrity, DNA damage, or elevated levels of intracellular reactive oxygen species. When considered together, the results presented here raise the intriguing prospect that spermatozoa exposed to a short-term PFAS exposure period potentially harbor an alternate stress signal that is delivered to the embryo upon fertilization. PFAS are synthetic chemicals widely used in non-stick cookware, food packaging, and firefighting foam. Such extensive use has led to concerning levels of environmental contamination and reports of associations with a spectrum of negative health outcomes, including testicular cancer and reduced semen quality. To investigate the effects of PFAS on male reproduction, we incubated mouse sperm in a cocktail of nine PFAS at environmentally relevant concentrations before checking for a range of functional outcomes. This treatment strategy was not toxic to the sperm; it did not kill them or reduce their motility, nor did it affect their fertilization capacity. However, we did observe developmental delays among pre-implantation embryos created using PFAS-treated sperm. Such findings raise the intriguing prospect that PFAS-exposed sperm harbor a form of stress signal that they deliver to the embryo upon fertilization.

Sensitive Methods to Detect Single-Stranded Nucleic Acids of Food Pathogens Based on Cell-Free Protein Synthesis and Retroreflection Signal Detection.

Cell-free protein synthesis (CFPS) has recently gained considerable attention as a new platform for developing methods to detect various molecules, ranging from small chemicals to biological macromolecules. Retroreflection has been used as an alternative signal to develop analytical methods because it can be detected by using a simple instrument comprising a white light source and a camera. Here, we report a novel reporter protein that couples the capability of CFPS and the simplicity of retroreflection signal detection. The design of the reporter was based on two pairs of protein-peptide interactions, SpyCatcher003-SpyTag003 and MDM2-PMI(N8A). MDM2-MDM2-SpyCatcher003 was decided as the reporter protein, and the two peptides, SpyTag003 and PMI(N8A), were immobilized on the surfaces of retroreflective Janus particles and microfluidic chips, respectively. The developed retroreflection signal detection system was combined with a previously reported CFPS reaction that can transduce the presence of a single-stranded nucleic acid into protein synthesis. The resulting methods were applied to detect 16S rRNAs of several foodborne pathogens. Concentration-dependent relationships were observed over a range of 10° fM to 102 pM, with the limits of detection being single-digit femtomolar concentrations. Considering the designability of the CFPS system for other targets, the retroreflection signal detection method will enable the development of novel methods to detect various molecules.

Deleting a Signal: Evidence from Pre-Employment Credit Checks

Abstract We study the removal of information from a market, such as a job-applicant screening tool. We characterize how removal harms groups with relative advantage in that information: typically those for whom the banned information is most precise relative to alternative signals. We illustrate this using recent bans on employers' use of credit report data. Bans decrease job-finding rates for Black job-seekers by 3 percentage points and increase involuntary separations for Black new hires by 4 percentage points, primarily because other screening tools, such as interviews, have around 60% higher standard deviation of signal noise for Black relative to white job-seekers.

A hybrid traffic controller system based on flower pollination algorithm and type-2 fuzzy logic optimized with crow search algorithm for signalized intersections

In this study, a hybrid traffic signal control (HTSC) system based on phase and time optimization was developed. The Flower Pollination Algorithm (FPA) approach was used for phase optimization, while Type-2 Fuzzy Logic, optimized with the Crow Search Algorithm (CSA), was utilized for time optimization. The hybrid system's performance was investigated using nine different traffic conditions and four different intersection geometries. The hybrid system was compared with three controller systems which are a fixed-time signal controller, a signal controller based on the FPA approach (FPA_TSC), and the optimized Type-1 fuzzy logic signal controller (Type-1 FL-TSC). The HTSC approach achieved the best performance with about 32% improvement over the fixed-time traffic controller and it showed 5% and 6% better performance than the FPA_TSC and Type-1 FL-TSC, respectively. Considering the performance of the new hybrid system, it is effective in minimizing delays and driver dissatisfaction occurring from signalization. It also contributes to the reduction of emissions and fuel consumption. The HTSC approach can be used as an alternative signal control method in the control of intersections with high traffic volume due to its fast and effective performance.

Abstract IA21: Mechanisms of Resistance to HER2-Targeted Therapies in HER2-positive Breast Cancer

Abstract Recent advancements in HER2-targeted therapies for HER2+ BC have revolutionized patient outcome. Yet, intrinsic and acquired resistance, especially in the advanced setting remains a clinical challenge. In the era of precision oncology, better understanding of these mechanisms of resistance is key to identifying new strategies to overcome resistance and for developing personalized treatment approaches. Our recent studies suggest that a subset of HER2+ BCs, associated with high and homogeneous levels of HER2 gene amplification, protein, and activity, are addicted to HER2 and may therefore benefit from chemotherapy-sparing HER2-targeted regimens. However, even in such tumors, constitutive activation of the PI3K/AKT pathway due to deregulations in the downstream PI3K pathway can lead to resistance. In all HER2+ BCs, failure to achieve a comprehensive blockade of the HER receptor layer is one of the major mechanisms of resistance due to the functional redundancy of the HER receptors and compensatory signaling within the pathway. But, in some cases, effective inhibition of HER receptors might be challenged by molecular masking of the receptors (e.g., MUC4) or by epi/genetic or post-translational alterations in the receptors itself (e.g., HER2 L755S, p95HER2). Indeed, we recently reported that acquisition of HER2 L755S, either alone or together with PIK3CA mutation, and hyperactive EGFR signaling due to acquired EGFR amplification or excess HER ligands are associated with resistance to HER2-targeted therapy, especially tyrosine kinase inhibitors. Likewise, clinically, HER mutations have been reported to be further enriched in the metastatic vs. primary HER2+ tumors. When HER2 does remain sustainably inhibited by HER2-targeted agents, resistance may arise due to the emergence of alternative signaling pathways transmitting compensatory proliferative and survival signals, such as ER, receptor tyrosine kinases, or downstream/intracellular signaling. Further, the emergence of metabolic pathways as alternative pathways of resistance have also been documented. We recently reported the activation of the cholesterol biosynthetic mevalonate (MVA) pathway as an escape mechanism that provides alternative signals through the YAP/TAZ-mTORC1-survivin axis to evade HER2 blockade. This resistance could be overcome using MVA pathway inhibitors (e.g., statins). Additionally, activation of the cell cycle regulatory complex cyclin D1/CDK4 has been shown to be associated with HER2-targeted therapy resistance, which could be exploited as a potential therapeutic vulnerability by using CDK4/6 inhibitors. Finally, response to HER2-targeted therapy could potentially be also modulated by the tumor microenvironment itself, including components of the host immune system and extracellular matrix. Together, a better understanding of the underlying mechanisms of resistance in the context of tumor and host biology, and treatment setup is fundamental to develop new treatment strategies and to guide patient stratification for personalized treatments and improved patient outcomes. Citation Format: Jamunarani Veeraraghavan, Fu-Tien Liao, Lanfang Qin, Tia Gordon, Alekya Raghavan, Caroline Sabotta, Rachel Kaplan, Carolina Gutierrez, C. Kent Osborne, Mothaffar F. Rimawi, Rachel Schiff. Mechanisms of Resistance to HER2-Targeted Therapies in HER2-positive Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA21.

Increasing Long-Term Memory as an Early Warning Signal for a Critical Transition

Abstract In recent years, various early warning signals of critical transition have been presented, such as autocorrelation at lag 1 [AR(1)], variance, the propagator based on detrended fluctuation analysis (DFA-propagator), and so on. Many studies have shown that the climate system has the characteristics of long-term memory (LTM). Will the LTM characteristics of the climate system change as it approaches possible critical transition points? In view of this, the present paper first studies whether the LTM of several folding (folded bifurcation) models changes consistently as they approach their critical points slowly by the rescaled range (R/S) analysis. The results of numerical experiments show that when the control parameters of the folding model are close to its critical threshold, the Hurst exponent H exhibits an almost monotonic increase (significance level α = 0.05). We compare the performance of R/S with the existing indicators, including AR(1), variance, and DFA-propagator, and find that R/S is a perfectly valid alternative. When there is no extra false noise, AR(1) and variance have good early warning effects. After the addition of extra Gaussian white noise of different intensities, the values of AR(1) and variance change significantly. As a result, the DFA-propagator based on AR(1) calibration also changed significantly. Compared with the other three indicators, the early warning effect of H has stronger ability to resist the interference of external false signals. To further verify the validity of increasing H, paleoclimate reconstruction of Cariaco Basin sediment core grayscale record with long trends filtered out is studied by R/S analysis. The other three early warning signals are calculated in the same way. The data contain a well-known abrupt climate change: the transition between the Younger Dryas (YD) and the Holocene. We find that approximately 300 years before this abrupt climate change occurred, before 11.7 kyr BP, the LTM exponents for Cariaco Basin deglacial grayscale data present an obvious increasing trend at a significant level of α = 0.05. Meanwhile, the variation trend of H and DFA-propagator is basically similar. This shows that increasing H by R/S analysis is an effective early warning signal, which indicates that a dynamic system is approaching its possible critical transition points; H is a completely valid alternative signal for AR(1) and DFA-propagator. The main conclusion of this paper is based on numerical experiments. The precise relationship between H and the stability of the underlying state approaching the transition needs to be further studied. Significance Statement Dynamic systems have critical transition points, and these systems will suddenly change from a stable state to another alternative one beyond these points. Using several simple theoretical models and paleoclimate data, we study whether the characteristics of long-term memory, which are ubiquitous in complex systems in nature and society, change as a system approaches its critical transition point. The results show that the long-term memory of a dynamic system increases significantly with the approach of the critical point, whether in theoretical models or in paleoclimate data.