Feedback Loop Research Articles

Revolutionizing Knowledge Synthesis: Introducing AI-Enhanced Collaborative Theory (AIECT)

In an era of unprecedented data development, standard literature review approaches can result in information overload and missed chances for theoretical innovation. This paper introduces AI-Enhanced Collaborative Theory (AIECT), a paradigm for dynamic collaboration between artificial intelligence (AI) systems and human researchers to improve knowledge synthesis and theoretical progress. AIECT focuses on the intersection of human intuition and AI capabilities, including essential components like dynamic co-creation, iterative feedback loops, contextual intelligence, and ethical frameworks. Empirical experiments show that AIECT can significantly increase the efficiency and depth of literature reviews and theory creation, showing its potential to revolutionize research processes and address information overload concerns. While limitations such as sample size and the need for additional validation are acknowledged, the findings indicate that AIECT represents a transformative approach to academic inquiry, encouraging innovative, ethical, and nuanced research techniques. By safely integrating AI, AIECT sets the way for advances in knowledge synthesis and provides a systematic foundation for future scholarly endeavors in various domains.

Interactions between soil and other environmental variables modulate forest expansion and ecotone dynamics in humid savannas of Central Africa.

Forest expansion into savanna is a pervasive phenomenon in West and Central Africa, warranting comparative studies under diverse environmental conditions. We collected vegetation data from the woody and grassy components within 73 plots of 0.16 ha distributed along a successional gradient from humid savanna to forest in Central Africa. We associated spatially collocated edaphic parameters and fire frequency derived from remote sensing to investigate their combined influence on the vegetation. Soil texture was more influential in shaping savanna structure and species distribution than soil fertility, with clay-rich soils promoting higher grass productivity and fire frequency. Savanna featuring woody aboveground biomass surpassing 40 Mg ha-1 could escape the grass-fire feedback loop, by depressing grass biomass below 4 Mg ha-1. This thicker woody layer also favoured the establishment of fire-tolerant forest pioneers, which synergically contributed to the expansion of forests. Conversely, savannas below this fire suppression threshold sustained a balance between trees and grasses through the grass-fire feedback mechanism. This hysteresis loop, particularly pronounced on clayey soils, suggests that the contrast between grassy savanna and young forests might represent alternative ecosystem states, although savannas with low woody biomass remained vulnerable to forest edge encroachment.

GPR56 facilitates hepatocellular carcinoma metastasis by promoting the TGF-β signaling pathway

The metastasis of hepatocellular carcinoma (HCC) poses a significant threat to the survival of patients. G protein-coupled receptor 56 (GPR56) has garnered extensive attention within malignant tumor research and plays a crucial role in cellular surface signal transmission. Nonetheless, its precise function in HCC remains ambiguous. Our investigation reveals a notable rise in GPR56 expression levels in human HCC cases, with heightened GPR56 levels correlating with unfavorable prognoses. GPR56 regulates TGF-β pathway by interacting with TGFBR1, thereby promoting HCC metastasis. At the same time, GPR56 is subject to regulation by the canonical cascade of TGF-β signaling, thereby establishing a positive feedback loop. Furthermore, the combination application of TGFBR1 inhibitor galunisertib (GAL) and GPR56 inhibitor Dihydromunduletone (DHM), significantly inhibits HCC metastasis. Interventions towards this signaling pathway could offer a promising therapeutic approach to effectively impede the metastasis of GPR56-mediated HCC.

Real-time hybrid testing using iterative control for periodic oscillations

Real-time hybrid testing is a method in which a substructure of the system is realized experimentally and the rest numerically. The two parts interact in real time to emulate the dynamics of the full system. Such experiments, however, are often difficult to realize as the actuators and sensors, needed to ensure compatibility and force–equilibrium conditions at the interface, can seriously affect the predicted dynamics of the system and result in stability and fidelity issues. The traditional approach of using feedback control to overcome the additional unwanted dynamics is challenging due to the presence of an outer feedback loop, passing interface displacements or forces to the numerical substructure. We, therefore, advocate for an alternative approach, removing the problematic interface dynamics with an iterative scheme to minimize interface errors, thus, capturing the response of the true assembly. The technique is examined by hybrid testing of a bench-top four-storey building with different interface configurations, where using conventional hybrid measurement techniques is very challenging. A case where the physical part exhibits nonlinear restoring force characteristics is also considered. These tests show that the iterative approach is capable of handling even scenarios which are theoretically infeasible with feedback control.

Isotopic seasonality of fluvial-derived greenhouse gases implies active layer deepening

Abstract Climate change in the northern circumpolar regions is rapidly thawing organic-rich permafrost soils, releasing substantial dissolved CO2 and CH4 into fluvial systems. This mobilization impacts local ecosystems and global climate feedback loops, playing a crucial role in the Arctic carbon cycle. Here, we analyze the stable carbon (δ13C) and radiocarbon (F14C) isotopic composition of dissolved CO2 and CH4 in the Sagavanirktok and Kuparuk River watersheds on the North Slope, Alaska. By examining spatial and seasonal variations in these isotopic signatures, we identify patterns of carbon release and transport along the river continuum. We find consistent CO2 isotopic signatures across the fluvial continuum, reflecting a mixture of geogenic and biogenic sources integrated throughout the watershed. Bayesian mixing models further demonstrate a systematic depletion in 13C and 14C signatures of dissolved CO2 sources from spring to fall, indicating increasing contributions of aged carbon as the active layer deepens seasonally. This seasonal deepening allows percolating groundwater to access deeper, older soil horizons, transporting CO2 produced by aerobic and anaerobic soil respiration to streams and rivers. In contrast, we observe no clear relationships between the 13C and 14C compositions of dissolved CH4 and landscape properties. Given the reduced solubility of CH4, which facilitates outgassing and limits its transport in aquatic systems, the isotopic signatures are likely indicative of localized contributions from streambeds, adjacent water saturated soils, and lake outflows. Our study demonstrates that dissolved greenhouse gases are sensitive indicators of the release of old carbon from thawing permafrost and serve as early warning signals for permafrost carbon feedback. It establishes a crucial baseline for understanding their role in regional carbon cycling and Arctic environmental change.

The Scribble-SGEF-Dlg1 complex regulates E-cadherin and ZO-1 stability, turnover and transcription in epithelial cells.

SGEF (also known as ARHGEF26), a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of both E-cadherin and ZO-1 (also known as TJP1) protein levels. However, the molecular mechanisms involved in the regulation of this pathway are not known. Here, we describe a novel signaling pathway governed by the Scribble-SGEF-Dlg1 complex. Our results show that the three members of the ternary complex are required to maintain the stability of the apical junctions, ZO-1 protein levels and tight junction (TJ) permeability. In contrast, only SGEF is necessary to regulate E-cadherin levels. The absence of SGEF destabilizes the E-cadherin-catenin complex at the membrane, triggering a positive feedback loop that exacerbates the phenotype through the repression of E-cadherin transcription in a process that involves the internalization of E-cadherin by endocytosis, β-catenin signaling and the transcriptional repressor Slug (also known as SNAI2).

Fostering TBL Success at Alfaisal University: A Complex Adaptive Systems Approach.

This study explores the implementation of Team-Based Learning (TBL) at Alfaisal University's College of Medicine through the lens of Complex Adaptive Systems (CAS) theory. The research question investigates how the application of CAS principles can enhance the implementation and effectiveness of TBL in medical education. The study employed a convergent parallel mixed methods longitudinal design, integrating quantitative performance metrics and qualitative themes. Quantitative analysis revealed modest improvements in individual and team-based learning scores, with a promising trend of students moving from the lower to the higher quartiles over time. Qualitative insights aligned with CAS principles, highlighting the adaptive implementation, emergent outcomes, self-organization, positive feedback loops, and depth of learning facilitated by TBL. The findings demonstrate the value of a CAS-informed approach in navigating the complexities of educational change and fostering a more resilient and adaptive educational model. The study contributes to the understanding of how CAS theory can guide the successful implementation of innovative pedagogies like TBL in medical education.

Innovating Nephrology Point-of-Care Ultrasonography Education: Artificial Intelligence-Assisted Curriculum Integration with Human Expert Feedback Loops

Innovating Nephrology Point-of-Care Ultrasonography Education: Artificial Intelligence-Assisted Curriculum Integration with Human Expert Feedback Loops

A framework for digital twin integration in biofabrication and a scaffold 3D bioplotting case study

Biofabrication, which integrates biological sciences with advanced manufacturing, is vital for innovations in tissue engineering and regenerative medicine. One primary consideration in this domain is ensuring consistent, scalable, and adaptable processes that are amenable to clinical translation. Toward this, this paper introduces a new framework for digital twin integration in biofabrication. Digital twins, which are real-time virtual replicas of physical systems, can facilitate comprehensive monitoring, accurate prediction, and effective optimization to enable robust biofabrication processes and systems. The proposed framework incorporates major building blocks for implementing digital twins for biofabrication, including comprehensive data acquisition and analysis using sophisticated sensors to integrate biological, material, and process data; advanced modeling methods utilizing traditional and machine learning algorithms to refine process parameters; and feedback loop for real-time process adjustments. The first phase of the framework is demonstrated through a case study highlighting process optimization of 3D bioplotting of polycaprolactone (PCL) scaffolds. The digital twin’s insights streamline decisions on bioplotting parameters and post-processing, ensuring that the printed scaffold meets the desired mechanical and biological properties, thereby significantly enhancing cell proliferation and printing resolution. Key benefits of this approach include optimized biofabrication outcomes by integrating physical and biological models, promoting scalability and reproducibility with an accelerated research and development phase. This work underlines the promise of digital convergence in biofabrication, which can accelerate advancements in regenerative medicine and tissue engineering.

The Capability to Aspire: An Agentive Model

ABSTRACT Drawing on Sen’s conceptual refinements of agency, in particular the distinction between agency freedom and agency achievement, this article highlights the existence of a feedback loop between agency and the capability to aspire. To explore this loop, the author uses John Dewey’s praxeological approach, bringing institutions into the “Capability Approach” along with situated agency. Against this background, she develops an agentive model of the capability to aspire, where the latter is nurtured by the longitudinal and lateral dimensions of experience. While the longitudinal dimension involves temporal processes driven by creative continuity (between past, present and future), the lateral dimension involves relational processes driven by social interactions (between a person and her environment). Institutions are an important part of that environment. By propagating social norms that define roles and behaviours in society, they provide a matrix for individual and collective aspirations, especially for people with fewer individual resources. But as Sen has pointed out, the moral ideals pursued by institutions do not necessarily translate into concrete achievements. This is why Dewey invites us to subject them to an ongoing critical inquiry that confronts their goals to their effective role in people’s lived experience, with the aim to transform them if necessary. The article concludes by discussing the implications of such a transformative inquiry and its potentially empowering effect in voicing aspirations and articulating new ones.

Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy

Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory Tcells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms "M2-like" TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ Tcells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses.

The integrated behavioral model of mental health help seeking (IBM-HS): A health services utilization theory of planned behavior for accessing care.

This article introduces the integrated behavioral model of mental health help seeking (IBM-HS), a theoretical model for understanding the constructs (e.g., systemic, predisposing, and enabling factors; mental health literacy; illness perceptions; perceived need; stigma; shame; perceived benefits, motivation) that influence people's decision making around seeking professional mental health care and their ultimate access to formal treatment. The IBM-HS is a help-seeking-specific adaptation of the empirically supported integrated behavioral model and integrative model, which are themselves evolutions of the theory of planned behavior and theory of reasoned action. The IBM-HS posits that help-seeking determinants (e.g., structural forces; cultural influences; past help-seeking experience; evaluated need; mental health perceptions, knowledge, and skills; social support) influence help-seeking beliefs (i.e., outcome beliefs, experiential beliefs, beliefs about others' expectations, beliefs about others' behavior, logistical beliefs), which in turn determine their respective help-seeking mechanisms (i.e., attitude, perceived norm, personal agency). These mechanisms collectively influence help-seeking intention, which drives prospective help-seeking behavior, subject to the moderating effects of determinants. Finally, prospective behavior has reciprocal feedback loop effects on certain determinants and beliefs. This article describes the need for the IBM-HS, the model's constructs and their interrelations, measurement considerations, and how the model can be used by scholarly and applied users to systematically understand people's intention to seek professional mental health care services and what helps or hinders them from utilizing this care. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A wideband high-PSR OCL LDO using a gain-relaxed OTA featuring dynamic complex zeros frequency compensation

This article proposes an Output-Capacitor-Less (OCL) Low-Dropout (LDO) regulator with an assisted positive feedback loop technique, which mimics a negative resistance, along with a single common-gate stage. Conventional techniques utilize multistage high-gain OTA to achieve a high DC loop gain. However, such an OTA suffers from high power consumption and sophisticated frequency compensation mechanisms. Instead, the use of a single-stage relatively low-gain OTA helps to extend the bandwidth. Then, the overall DC loop gain is maximized by the proposal of a novel negative resistance circuit. To further improve the PSR, a bulk-driven ripple canceling path that is insensitive to process corners is proposed making the LDO suitable for high-PSR applications. Stability is another challenge in the design of OCL LDOs due to its associated complex poles. We propose a new frequency compensation technique by introducing two complex zeros to eliminate these complex poles. Hence, the overall stability is improved. Since these complex poles location vary from light to heavy loads, the proposed zeros dynamically change accordingly. Besides, this suggested mechanism has been analyzed using the generalized time-and-transfer constants (TTCs) circuit analysis technique. Under heavy load conditions, the suggested LDO has attained phase and gain margins of 62.8° and 29 dB, respectively. Moreover, Monte Carlo simulations along with process and temperature variations have been investigated to prove the reliability of such a frequency compensation technique. The proposed LDO has been implemented in 65 nm CMOS technology node with a short pass transistor length of 100nm. The simulation results reveals that the LDO draws 299.4μA of quiescent current under light load conditions and 296.8μA under heavy load conditions (including the bandgap voltage reference). The suggested LDO functions at 1.2V supply voltage, delivers 0.93V output voltage and can handle a load current up to 10mA with load regulation of 17μV/mA, line regulation of 2.22mV/V, and PSR of −48.7dB at low frequencies. The PSR at 1MHz is at least −32.5dB which is superior to the reported recent LDOs.

Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation

Abstract Background Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. Methods The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. Results We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. Conclusions Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Directly modulated FMCW tunable laser with highly linear frequency chirp and narrow linewidth

Frequency-modulated continuous-wave light detection and ranging (FMCW LiDAR) is a promising technology for long-range, high-accuracy, stray-light-immune distance and velocimetry sensing. To achieve this, a precisely chirped and highly coherent laser source is required. In this work, we propose to generate a highly linear frequency chirp by utilizing an intracavity phase modulator with high linearity and demonstrate a proof-of-concept fully integrated monolithic FMCW laser source based on an InP generic platform. By electrically modulating the intracavity phase modulator at a repetition rate of 100 kHz, a 1.85 GHz chirp range with root mean square (RMS) frequency nonlinearity down to 1.8 MHz is achieved without the need of external feedback loop or predistortion. Meanwhile, the laser shows a 51 nm tuning range with a linewidth down to 16 kHz. By taking advantage of the high-speed electro-optical effects, fast frequency modulation with repetition rate of up to 1 MHz is realized with a frequency chirp range of ∼1.65 GHz and RMS frequency nonlinearity of ∼12 MHz. We demonstrate its feasibility for LiDAR through in-fiber ranging at a distance of 50 m, where a 51 cm resolution is directly achieved.

Hot and cold exposure triggers distinct transcriptional and behavioral responses in laboratory-inbred pond snails

Animals exhibit remarkable behavioral and molecular adaptations to cope with thermal stressors, which are crucial for survival in variable environments that are exacerbated by climate change. Aquatic poikilotherms like our model organism—the pond snail Lymnaea stagnalis—face significant challenges due to their dependence on external temperatures. Our study provides valuable insights into the different behavioral and molecular responses of lab-inbred snails to cold and heat shock stressors (i.e., 4 °C and 30 °C), particularly in the context of learning and memory formation. We found that while short-term (1 h) cold exposure transiently upregulated the expression levels of HSP70 and HSP40 in the snail’s central ring ganglia, prolonged cold exposure (24 h) resulted in a significant downregulation of LymMIPII and an upregulation of LymMIPR. These data suggest, albeit at the transcriptional level, the existence of a negative feedback loop necessary for sustaining cellular functions when metabolic demands might shift towards conserving energy during prolonged cold exposure. At the behavioral level, we found that, compared to heat shock, cold exposure did not result in a Garcia effect (i.e., a “special form” of conditioned taste aversion). The difference in memory outcomes was associated with changes in the expression levels of selected targets involved in neuronal plasticity and the stress response. While both cold and heat shock upregulated the HSP levels in the snail's central ring ganglia, cold exposure did not affect the expression levels of the neuroplasticity genes LymGRIN1 and LymCREB1, contrasting with heat shock’s neurogenic effects. Overall, this study provides insights into L. stagnalis's adaptive responses to thermal stressors, emphasizing different molecular strategies for coping with heat versus cold challenges in aquatic environments. These findings contribute to our understanding of thermal biology and stress physiology in aquatic organisms, underscoring the importance of molecular mechanisms in shaping species' resilience in dynamic environments.

A theoretical model for focal adhesion and cytoskeleton formation in non-motile cells

To function and survive cells need to be able to sense and respond to their local environment through mechanotransduction. Crucially, mechanical and biochemical perturbations initiate cell signaling cascades, which can induce responses such as growth, apoptosis, proliferation and differentiation. At the heart of this process are actomyosin stress fibres (SFs), which form part of the cell cytoskeleton, and focal adhesions (FAs), which bind this cytoskeleton to the extra-cellular matrix (ECM). The formation and maturation of these structures (connected by a positive feedback loop) is pivotal in non-motile cells, where SFs are generally of ventral type, interconnecting FAs and producing isometric tension. In this study we formulate a one-dimensional bio-chemo-mechanical continuum model to describe the coupled formation and maturation of ventral SFs and FAs. We use a set of reaction–diffusion-advection equations to describe three sets of biochemical events: the polymerisation of actin and subsequent bundling into activated SFs; the formation and maturation of cell-substrate adhesions; and the activation of signaling proteins in response to FA and SF formation. The evolution of these key proteins is coupled to a Kelvin-Voigt viscoelastic description of the cell cytoplasm and the ECM. We employ this model to understand how cells respond to external and intracellular cues in vitro and are able to reproduce experimentally observed phenomena including non-uniform cell striation and cells forming weaker SFs and FAs on softer substrates.

Glycated hemoglobin, type 2 diabetes, and poor diabetes control are positively associated with impulsivity changes in aged individuals with overweight or obesity and metabolic syndrome.

Impulsivity has been proposed to have an impact on glycemic dysregulation. However, it remains uncertain whether an unfavorable glycemic status could also contribute to an increase in impulsivity levels. This study aims to analyze associations of baseline and time-varying glycemic status with 3-year time-varying impulsivity in older adults at high risk of cardiovascular disease. A 3-year prospective cohort design was conducted within the PREDIMED-Plus-Cognition substudy. The total population includes 487 participants (mean age = 65.2 years; female = 50.5%) with overweight or obesity and metabolic syndrome. Insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), presence of type 2 diabetes mellitus, and type 2 diabetes control were evaluated. Impulsivity was measured using the Impulsive Behavior Scale questionnaire and various cognitive measurements. Impulsivity z-scores were generated to obtain Global, Trait, and Behavioral Impulsivity domains. Linear mixed models were used to study the longitudinal associations across baseline, 1-year, and 3-year follow-up visits. HOMA-IR was not significantly related to impulsivity. Participants with higher HbA1c levels, type 2 diabetes, and poor control of diabetes showed positive associations with the Global Impulsivity domain over time, and those with higher HbA1c levels were further related to increases in the Trait and Behavioral Impulsivity domains over the follow-up visits. These results suggest a potential positive feedback loop between impulsivity and glycemic-related dysregulation.

Optimizing Serverless Function Orchestration for Complex Workflows in Cloud Platforms

Purpose: This paper aims to investigate ways of increasing the efficiency of various workloads of serverless function orchestration in cloud systems while decreasing latency and optimizing resources. Materials and Methods: The report suggests adaptive learning systems and a feedback loop framework for managing the orchestrating serverless environment. Findings: It has also been affirmed that case studies help validate the framework rather than presenting the practical implications of the proposed techniques. Implications to Theory, Practice and Policy: The paper recommends focusing on managing performance, dependencies, and expenses in serverless function orchestration by employing adaptive learning systems and feedback loop frameworks.

Autophagy, aging, and age-related neurodegeneration.

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.