ATF3 Protein

ATF3 (Activating Transcription Factor 3) in Neurodegenerative Diseases

<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">ATF3 Protein</th>
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<td class="label">Symbol</td>
<td><strong>ATF3</strong></td>
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<td class="label">Full Name</td>
<td>ATF3</td>
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<td class="label">Type</td>
<td>Protein</td>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=ATF3" target="_blank">Search UniProt</a></td>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">251 edges</a></td>
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Introduction

ATF3 (Activating Transcription Factor 3) in Neurodegenerative Diseases

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">ATF3 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATF3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ATF3</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=ATF3" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">251 edges</a></td>
</tr>
</table>

Introduction

Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP response element-binding (CREB) protein family of transcription factors that plays a critical role in the cellular response to stress, injury, and pathological stimuli. Originally identified as an immediate-early gene induced by serum stimulation in fibroblasts, ATF3 has since emerged as a key regulator of cellular homeostasis with particular significance in the nervous system PMID: 7743994(https://pubmed.ncbi.nlm.nih.gov/7743994/). The protein functions as a molecular hub that integrates various stress signals and modulates gene expression programs governing cell survival, death, inflammation, and adaptation. In the context of neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)—ATF3 has been implicated as both a protective response and a contributor to pathology, depending on cellular context and disease stage. [@pmid2017a]

Recent advances in molecular neuroscience have highlighted ATF3 as a dynamically regulated transcription factor that responds rapidly to neurotoxic stimuli, including protein aggregation, oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation. The bidirectional nature of ATF3 function—sometimes protective and sometimes detrimental—has made it an attractive target for understanding disease mechanisms and developing therapeutic interventions. This article provides a comprehensive review of ATF3's structure, function, and specific roles in major neurodegenerative disorders. [@pmid2018]

Gene Structure and Chromosomal Localization

The human ATF3 gene (Gene ID: 467) is located on chromosome 1q32.3 and spans approximately 15 kilobases. The gene consists of four exons and three introns, with the coding sequence distributed across all exons PMID: 7743994(https://pubmed.ncbi.nlm.nih.gov/7743994/). Alternative splicing gives rise to multiple ATF3 transcript variants, although the predominant isoform in most tissues encodes a 181-amino-acid protein of approximately 22 kDa. [@pmid2019]

The ATF3 promoter region contains multiple regulatory elements that respond to diverse stimuli. The proximal promoter harbors consensus binding sites for activator protein-1 (AP-1), CREB, and NF-κB, allowing integration of signals from various stress-activated pathways PMID: 15802548(https://pubmed.ncbi.nlm.nih.gov/15802548/). Additionally, the promoter contains a TATA box and initiator element that direct transcription initiation. The ATF3 gene can be induced through multiple signaling cascades, including the mitogen-activated protein kinase (MAPK) pathways, protein kinase C (PKC) pathways, and calcium-dependent pathways, reflecting its role as a broad-spectrum stress response gene. [@pmid2020]

Protein Structure and Functional Domains

ATF3 possesses a modular architecture consisting of distinct functional domains that mediate its transcriptional activity, DNA binding, and protein-protein interactions. The protein contains a basic region-leucine zipper (bZIP) domain at its C-terminus, which is essential for both DNA binding and dimerization PMID: 7583821(https://pubmed.ncbi.nlm.nih.gov/7583821/). The basic region (approximately 20 amino acids) contacts the DNA backbone and confers sequence-specific binding to ATF/CRE sites (TGACGTCA and related sequences), while the leucine zipper mediates homodimerization or heterodimerization with other bZIP proteins. [@pmid2020a]

The N-terminal region of ATF3 contains transcriptional regulatory domains that function as either activation or repression domains depending on context. This region interacts with various co-activators and co-repressors, including histone acetyltransferases (HATs), histone deacetylases (HDACs), and components of the basal transcription machinery PMID: 19344639(https://pubmed.ncbi.nlm.nih.gov/19344639/). The flexibility of the N-terminal domain allows ATF3 to function as either a transcriptional activator or repressor, a property that is heavily influenced by post-translational modifications, dimerization partners, and cellular context. [@pmid2021]

ATF3 can form homodimers or heterodimers with related bZIP proteins, including ATF2, JunB, c-Jun, and CREB. The choice of dimerization partner significantly impacts ATF3's DNA binding specificity and transcriptional outcome. Heterodimerization with Jun family members typically enhances transcriptional activation, while certain combinations may produce repressive complexes PMID: 25982152(https://pubmed.ncbi.nlm.nih.gov/25982152/). [@pmid2021a]

Molecular Functions and Mechanisms of Action

Transcriptional Regulation

ATF3 functions primarily as a transcription factor that regulates the expression of genes involved in stress responses, cell cycle control, apoptosis, and inflammation. As a member of the ATF/CREB family, ATF3 binds to ATF/CRE sites in the promoter and enhancer regions of target genes, modulating their transcription in response to cellular signals PMID: 15802548(https://pubmed.ncbi.nlm.nih.gov/15802548/). [@pmid2022]

The transcriptional targets of ATF3 are extensive and context-dependent. In neuronal cells, ATF3 has been shown to regulate genes involved in the unfolded protein response (UPR), including BiP (GRP78), CHOP (GADD153), and XBP1 PMID: 27145997(https://pubmed.ncbi.nlm.nih.gov/27145997/). ATF3 also modulates expression of genes controlling apoptosis (e.g., BIM, PUMA, Bcl-2 family members), neuroprotection (e.g., BDNF, GDNF), and inflammation (e.g., cytokines, chemokines) PMID: 28706826(https://pubmed.ncbi.nlm.nih.gov/28706826/). [@pmid2022a]

Protein-Protein Interactions

Beyond its direct DNA binding activity, ATF3 exerts significant biological effects through protein-protein interactions. ATF3 interacts with various signaling molecules, transcriptional regulators, and structural proteins, positioning it as a node in cellular signaling networks. [@pmid2023]

One particularly important interaction involves ATF3's binding to components of the NF-κB pathway. ATF3 can repress NF-κB-dependent transcription by competing for co-activators or by recruiting repressive complexes to NF-κB target genes PMID: 35514082(https://pubmed.ncbi.nlm.nih.gov/35514082/). This interaction has significant implications for neuroinflammation, as NF-κB is a major regulator of pro-inflammatory gene expression in glial cells and neurons.

ATF3 also interacts with histone deacetylases (HDACs), particularly HDAC1 and HDAC3, to form repressive complexes that silence gene expression PMID: 32203469(https://pubmed.ncbi.nlm.nih.gov/32203469/). Conversely, ATF3 can recruit HATs such as p300/CBP to activate transcription. The balance between these interactions determines whether ATF3 functions as an activator or repressor in specific contexts.

Regulation by Post-Translational Modifications

ATF3 activity and stability are regulated by several post-translational modifications. Phosphorylation of ATF3 at serine/threonine residues influences its transcriptional activity, subcellular localization, and protein-protein interactions. Casein kinase 2 (CK2) phosphorylates ATF3 at multiple sites, enhancing its stability and transcriptional activity PMID: 33004825(https://pubmed.ncbi.nlm.nih.gov/33004825/).

Acetylation of ATF3 by p300/CBP modulates its DNA binding affinity and transcriptional properties. Additionally, sumoylation of ATF3 at lysine residues can alter its subcellular localization and influence its function as a transcriptional regulator. These modifications allow rapid modulation of ATF3 activity in response to changing cellular conditions without requiring de novo protein synthesis.

ATF3 in the Neuronal Stress Response

Induction by Cellular Stressors

Neurons are highly specialized cells with limited regenerative capacity, making them particularly vulnerable to various forms of cellular stress. ATF3 expression is rapidly induced in neurons following diverse stress stimuli, including excitotoxicity, oxidative stress, ER stress, metabolic stress, and physical injury PMID: 29246889(https://pubmed.ncbi.nlm.nih.gov/29246889/). This rapid induction positions ATF3 as an early responder that may determine whether neurons adapt to stress or undergo cell death.

In response to kainic acid-induced excitotoxicity, ATF3 expression is dramatically upregulated in hippocampal neurons, particularly in regions susceptible to seizure-induced damage PMID: 19344639(https://pubmed.ncbi.nlm.nih.gov/19344639/). Similarly, ATF3 is induced in motor neurons following axotomy and in dopaminergic neurons following toxic insults relevant to Parkinson's disease models.

Role in the Unfolded Protein Response

The accumulation of misfolded proteins in the ER triggers the unfolded protein response (UPR), a conserved adaptive pathway that aims to restore ER homeostasis or, if unsuccessful, initiate apoptosis. ATF3 is induced as part of the UPR and participates in both adaptive and pro-apoptotic branches of this response PMID: 27145997(https://pubmed.ncbi.nlm.nih.gov/27145997/).

During ER stress, ATF3 transcription is activated by the PERK-eIF2α-ATF4 pathway and the IRE1-XBP1 pathway. ATF3 then cooperates with ATF4 to induce expression of CHOP (GADD153), a transcription factor that promotes ER stress-induced apoptosis. However, ATF3 can also induce expression of ER chaperones and components of the ER-associated degradation (ERAD) system, suggesting a role in adaptation PMID: 31321087(https://pubmed.ncbi.nlm.nih.gov/31321087/).

Modulation of Apoptosis

The relationship between ATF3 and apoptosis is complex and context-dependent. ATF3 can promote or inhibit cell death depending on the cell type, nature of the stress signal, and interaction with other signaling pathways. In many contexts, ATF3 functions as a pro-apoptotic factor that sensitizes cells to death receptor activation or chemotherapeutic agents PMID: 28706826(https://pubmed.ncbi.nlm.nih.gov/28706826/).

In neurons, ATF3 has been shown to transcriptionally activate pro-apoptotic genes such as BIM and PUMA while repressing anti-apoptotic genes like BCL-2. However, ATF3 can also protect neurons under certain conditions by inducing expression of survival factors or by interfering with pro-death signaling pathways. This duality may reflect the need for careful balancing of survival and death decisions in neurons facing chronic stress.

ATF3 in Alzheimer's Disease

Overview of Alzheimer's Disease Pathology

Alzheimer's disease is the most common cause of dementia, characterized by extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau, synaptic loss, and widespread neuronal death. Neuroinflammation, featuring activation of microglia and astrocytes, contributes to disease progression PMID: 21135125(https://pubmed.ncbi.nlm.nih.gov/21135125/). ATF3 expression is altered in Alzheimer's disease brain tissue and in cellular and animal models of the disease, suggesting involvement in AD pathogenesis.

ATF3 and Amyloid-Beta Pathology

ATF3 responds to amyloid-beta accumulation, a central pathological feature of AD. In vitro studies demonstrate that Aβ peptides induce ATF3 expression in neurons and glia through activation of stress-activated protein kinases and NF-κB PMID: 21135125(https://pubmed.ncbi.nlm.nih.gov/21135125/). ATF3 induction occurs early in response to Aβ and may mediate some of the toxic effects of oligomeric and fibrillar Aβ species.

Transgenic mouse models of AD, including APP/PS1 and 3xTg-AD mice, show elevated ATF3 expression in vulnerable brain regions, particularly in neurons surrounding amyloid plaques PMID: 33723178(https://pubmed.ncbi.nlm.nih.gov/33723178/). This elevated ATF3 correlates with markers of ER stress and apoptosis, suggesting that ATF3 may contribute to Aβ-induced neuronal death. In contrast, ATF3 knockout mice crossed with AD models show conflicting results regarding amyloid pathology, with some studies suggesting increased plaque burden and others showing reduced neurotoxicity, underscoring the complexity of ATF3 function in AD.

ATF3 and Tau Pathology

Tau pathology, characterized by hyperphosphorylation, misfolding, and aggregation of tau protein into neurofibrillary tangles, is another hallmark of Alzheimer's disease. ATF3 expression is induced in neurons containing tau aggregates, and this induction may represent a response to proteostatic stress PMID: 33723178(https://pubmed.ncbi.nlm.nih.gov/33723178/).

Studies in cell culture models demonstrate that ATF3 can influence tau phosphorylation and aggregation. Overexpression of ATF3 enhances tau aggregation and toxicity, while knockdown or knockout of ATF3 reduces tau-induced cell death PMID: 30555575(https://pubmed.ncbi.nlm.nih.gov/30555575/). The mechanism may involve ATF3-mediated regulation of kinases and phosphatases that control tau phosphorylation, as well as modulation of autophagy and proteasome activity that influence tau clearance.

ATF3 in Neuroinflammation in Alzheimer's Disease

Neuroinflammation is increasingly recognized as a major contributor to AD pathogenesis, with activated microglia producing pro-inflammatory cytokines that promote neuronal dysfunction and death. ATF3 plays a complex role in regulating neuroinflammation, with context-dependent effects on microglial activation and cytokine production PMID: 35514082(https://pubmed.ncbi.nlm.nih.gov/35514082/).

In microglia, ATF3 is induced by Aβ and inflammatory stimuli. ATF3 can suppress NF-κB-mediated transcription of pro-inflammatory cytokines, suggesting an anti-inflammatory function PMID: 32203469(https://pubmed.ncbi.nlm.nih.gov/32203469/). However, ATF3 can also promote expression of certain chemokines and matrix metalloproteinases that contribute to neuroinflammatory damage. This duality suggests that ATF3's role in AD neuroinflammation may differ depending on disease stage and specific microglial phenotypes.

In astrocytes, ATF3 expression is induced by inflammatory cytokines and cellular stress. Astrocytic ATF3 may influence the supportive functions of astrocytes and their interactions with neurons, potentially affecting synaptic function and neuronal survival in AD PMID: 36342973(https://pubmed.ncbi.nlm.nih.gov/36342973/).

ATF3 in Parkinson's Disease

Overview of Parkinson's Disease Pathology

Parkinson's disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of intracytoplasmic inclusions called Lewy bodies, which are primarily composed of aggregated alpha-synuclein (αSyn) PMID: 24140019(https://pubmed.ncbi.nlm.nih.gov/24140019/). Motor symptoms including tremor, rigidity, and bradykinesia result from dopamine depletion in the striatum. In addition to alpha-synuclein pathology, mitochondrial dysfunction, oxidative stress, and neuroinflammation are central features of PD pathogenesis.

ATF3 and Alpha-Synuclein

ATF3 is strongly induced in response to alpha-synuclein accumulation and aggregation, both hallmarks of PD. In cellular models, overexpression of wild-type or pathogenic mutant αSyn triggers ATF3 expression through activation of ER stress pathways and oxidative stress responses PMID: 24140019(https://pubmed.ncbi.nlm.nih.gov/24140019/). ATF3 induction correlates with markers of cellular stress and precedes cell death in these models.

Studies in animal models of PD, including those using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), demonstrate robust ATF3 induction in dopaminergic neurons PMID: 34453067(https://pubmed.ncbi.nlm.nih.gov/34453067/). This induction may represent a neuroprotective response, as ATF3 can activate expression of genes involved in protein quality control and antioxidant defense. However, sustained or excessive ATF3 activation may contribute to dopaminergic neuron death.

Mitochondrial Dysfunction and Oxidative Stress

Mitochondrial dysfunction is a central pathogenic mechanism in PD, as evidenced by the identification of mutations in genes encoding mitochondrial proteins (PINK1, Parkin, DJ-1) in familial PD. ATF3 responds to mitochondrial stress and may link mitochondrial dysfunction to transcriptional responses that influence neuronal survival PMID: 34453067(https://pubmed.ncbi.nlm.nih.gov/34453067/).

In models of mitochondrial toxins relevant to PD (MPTP, rotenone, 6-OHDA), ATF3 expression is rapidly induced in dopaminergic neurons. This induction is mediated in part by activation of stress-activated kinases and may contribute to both protective and detrimental outcomes. ATF3 target genes include those involved in mitochondrial dynamics (fission and fusion), mitophagy, and antioxidant defense PMID: 29246889(https://pubmed.ncbi.nlm.nih.gov/29246889/).

Neuroprotection of Dopaminergic Neurons

Evidence suggests that ATF3 may exert neuroprotective effects in dopaminergic neurons under certain conditions. ATF3 can induce expression of neurotrophic factors such as BDNF and GDNF, which support neuronal survival and function PMID: 31321087(https://pubmed.ncbi.nlm.nih.gov/31321087/). Additionally, ATF3-mediated regulation of anti-apoptotic genes and autophagy may contribute to neuronal protection.

Studies using viral vector-mediated ATF3 overexpression in the substantia nigra have shown mixed results, with some indicating reduced dopaminergic neuron loss following toxic insult and others showing no effect or even increased toxicity PMID: 34453067(https://pubmed.ncbi.nlm.nih.gov/34453067/). These discrepancies may reflect differences in experimental models, ATF3 expression levels, and timing of intervention.

ATF3 in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the brain and spinal cord. ATF3 expression is induced in motor neurons in ALS models and in tissue from ALS patients, suggesting involvement in the disease process PMID: 36342973(https://pubmed.ncbi.nlm.nih.gov/36342973/).

In models of ALS using SOD1 mutants or TDP-43/C9orf72 pathology, ATF3 is rapidly induced in vulnerable motor neurons. This induction may represent a stress response that could be either protective or detrimental depending on context. ATF3 null mice show altered responses to motor neuron injury, highlighting the importance of ATF3 in motor neuron biology PMID: 29246889(https://pubmed.ncbi.nlm.nih.gov/29246889/).

Huntington's Disease

Huntington's disease is caused by expansion of CAG repeats in the huntingtin (HTT) gene, leading to production of mutant huntingtin protein that aggregates and causes neuronal dysfunction, particularly in striatal and cortical neurons. ATF3 expression is induced in models of Huntington's disease and in human HD brain tissue PMID: 32203469(https://pubmed.ncbi.nlm.nih.gov/32203469/).

The induction of ATF3 in HD may be triggered by mutant huntingtin-induced ER stress, oxidative stress, and mitochondrial dysfunction. ATF3 may contribute to disease progression by regulating genes involved in these processes or by influencing transcriptional programs that affect neuronal survival.

Therapeutic Implications

Targeting ATF3 for Neuroprotection

Given its central role in integrating stress responses and influencing cell fate decisions, ATF3 represents a potential therapeutic target for neurodegenerative diseases. Strategies aimed at modulating ATF3 expression or activity could potentially enhance neuronal survival under pathological conditions PMID: 36342973(https://pubmed.ncbi.nlm.nih.gov/36342973/).

However, the bidirectional nature of ATF3 function—sometimes protective and sometimes detrimental—presents a significant challenge for therapeutic targeting. Careful consideration of disease stage, specific pathology, and cellular context is essential. Enhancing ATF3 expression or activity may be beneficial early in disease when stress responses are adaptive, while suppressing ATF3 later may prevent excessive or prolonged stress responses that contribute to neuronal death.

Small Molecule Modulators

No selective ATF3 activators or inhibitors are currently available for clinical use. However, several compounds known to induce ATF3 expression have shown neuroprotective effects in preclinical models. These include:

• Celastrol: A triterpenoid from Thunder God Vine that induces ATF3 and demonstrates neuroprotective effects in models of PD and ALS PMID: 36342973(https://pubmed.ncbi.nlm.nih.gov/36342973/).
• Salubrinal: An ER stress modulator that enhances eIF2α phosphorylation and ATF3 induction, providing protection against protein aggregation toxicity.
• HDAC inhibitors: Compounds such as sodium valproate and SAHA can modulate ATF3 expression and have been tested in neurodegenerative disease models.

Gene Therapy Approaches

Gene therapy strategies targeting ATF3 or its transcriptional targets represent another therapeutic avenue. Viral vector-mediated delivery of ATF3, ATF3 mutants, or ATF3 target genes could potentially modulate stress responses in neurons.

Overexpression of specific ATF3 target genes involved in neuroprotection, such as neurotrophic factors or anti-apoptotic proteins, may provide benefits without the pleiotropic effects of broad ATF3 modulation. Conversely, knockdown of detrimental ATF3 targets could reduce neuronal loss.

Biomarker Potential

ATF3 expression in peripheral tissues or cerebrospinal fluid may have value as a biomarker of neuronal stress in neurodegenerative diseases. ATF3 mRNA and protein levels are detectable in blood cells and can be induced by systemic inflammation or neuroinflammation. However, the utility of ATF3 as a clinical biomarker remains to be established.

Conclusions and Future Directions

ATF3 has emerged as a critical regulator of the neuronal stress response with significant implications for neurodegenerative diseases. As a stress-inducible transcription factor, ATF3 integrates signals from diverse pathological stimuli—including protein aggregation, ER stress, oxidative stress, and neuroinflammation—to modulate gene expression programs governing cell survival and death.

In Alzheimer's disease, ATF3 responds to amyloid-beta and tau pathology, influencing neuronal vulnerability and neuroinflammatory responses. In Parkinson's disease, ATF3 induction by alpha-synuclein and mitochondrial toxins may determine the fate of dopaminergic neurons facing chronic stress. The dual nature of ATF3 function—sometimes protective and sometimes detrimental—reflects its role as a molecular switch that can tip the balance between adaptation and apoptosis.

Future research should focus on several key areas:

In summary, ATF3 represents a fascinating node in the cellular stress response network with significant relevance to neurodegenerative disease pathogenesis. Continued investigation of ATF3's functions and mechanisms may yield insights into disease mechanisms and therapeutic opportunities for conditions that currently lack effective disease-modifying treatments.

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Pathway Diagram

References

PMID: 7583821(https://pubmed.ncbi.nlm.nih.gov/7583821/) PMID: 7743994(https://pubmed.ncbi.nlm.nih.gov/7743994/) PMID: 15802548(https://pubmed.ncbi.nlm.nih.gov/15802548/) PMID: 19344639(https://pubmed.ncbi.nlm.nih.gov/19344639/) PMID: 21135125(https://pubmed.ncbi.nlm.nih.gov/21135125/) PMID: 24140019(https://pubmed.ncbi.nlm.nih.gov/24140019/) PMID: 25259924(https://pubmed.ncbi.nlm.nih.gov/25259924/) PMID: 25982152(https://pubmed.ncbi.nlm.nih.gov/25982152/) PMID: 27145997(https://pubmed.ncbi.nlm.nih.gov/27145997/) PMID: 28706826(https://pubmed.ncbi.nlm.nih.gov/28706826/) PMID: 29246889(https://pubmed.ncbi.nlm.nih.gov/29246889/) PMID: 30555575(https://pubmed.ncbi.nlm.nih.gov/30555575/) PMID: 31321087(https://pubmed.ncbi.nlm.nih.gov/31321087/) PMID: 32203469(https://pubmed.ncbi.nlm.nih.gov/32203469/) PMID: 33004825(https://pubmed.ncbi.nlm.nih.gov/33004825/) PMID: 33723178(https://pubmed.ncbi.nlm.nih.gov/33723178/) PMID: 34453067(https://pubmed.ncbi.nlm.nih.gov/34453067/) PMID: 35514082(https://pubmed.ncbi.nlm.nih.gov/35514082/) PMID: 36342973(https://pubmed.ncbi.nlm.nih.gov/36342973/) PMID: 37538347(https://pubmed.ncbi.nlm.nih.gov/37538347/)