Pathophysiological Research Research Articles

Human umbilical cord mesenchymal stem cells restore chemotherapy-induced premature ovarian failure by inhibiting ferroptosis in vitro ovarian culture system

BackgroundMesenchymal stem cells (MSCs) have shown potential in repairing chemotherapy-induced premature ovarian failure (POF). However, challenges such as stem cell loss and immune phagocytosis post-transplantation hinder their application. Due to easy and safe handling, in vitro ovarian culture is widely available for drug screening, pathophysiological research, and in vitro fertilization. MSCs could exhibit therapeutic capacity for ovarian injury, and avoid stem cell loss and immune phagocytosis in vitro tissue culture system. Therefore, this study utilizes an in vitro ovarian culture system to investigate the reparative potential of human umbilical cord mesenchymal stem cells (hUCMSCs) and their mechanism.MethodsIn this study, a chemotherapy-induced POF model was established by introducing cisplatin in vitro ovarian culture system. The reparative effects of hUCMSCs on damaged ovarian tissue were validated through Transwell chambers. Tissue histology examination, immunohistochemical staining, Western blotting, and RT-PCR were employed to evaluate the expression effects of hUCMSCs on ferroptosis and fibrosis-related genes during the process of repairing cisplatin-induced POF.ResultsCisplatin was found to activate ovarian follicles in vitro POF model. Transcriptomic sequencing analysis revealed that cisplatin could activate genes associated with ferroptosis. hUCMSCs alleviated cisplatin-induced POF by suppressing the expression of ferroptosis. Moreover, inhibiting ferroptosis by hUCMSCs also ameliorated ovarian hormone levels and reduced the expression of fibrosis-related factors α-SMA and COL-I in the ovaries.ConclusionsThis study confirms that cisplatin-induced ovarian damage via ferroptosis in vitro POF model, and hUCMSCs repair ovarian injury by inhibiting the ferroptosis pathway and suppressing fibrosis. This research contributes to evaluating the effectiveness of hUCMSCs in treating chemotherapy-induced POF by inhibiting ferroptosis in an in vitro ovarian culture system and provides a potential therapeutic strategy for chemotherapy-induced POF.

Long-Term Impacts of COVID-19 on Thyroid Health: Insights From Clinical Studies.

COVID-19 emerged in December 2019 and rapidly became a global pandemic. It has since been associated with the progression of various endocrine disorders, including thyroid disease. The long-term effects of this interplay have yet to be explored. This review explores the relationship between COVID-19 and thyroid diseases, emphasizing thyroid gland function and the clinical implications for managing thyroid disorders in infected individuals. This narrative review intends to provide insight into the scope of research that future clinical studies may aim to address regarding the long-term effects of COVID-19 infection on thyroid health. Keywords including "thyroid disease", "COVID-19", and "long-term" were used to search PubMed and Google Scholar for updated and relevant clinical research. COVID-19 affects the thyroid gland multifacetedly and includes direct viral invasion, immune-mediated damage, and hypothalamic-pituitary-thyroid axis disruption. Approximately 15% of COVID-19 patients experience thyroid dysfunction, which can present as thyrotoxicosis, hypothyroidism, or non-thyroidal illness syndrome (NTI). Noteworthy findings include inflammatory thyroiditis. Long-term effects, including those observed in children, include persistent hypothyroidism and exacerbated pre-existing thyroid-autoimmune conditions. Management of thyroid disorders in COVID-19 patients requires consideration: anti-thyroid drug (ATD) therapy used to treat hyperthyroidism in COVID-19 patients may need adjustment to prevent immunosuppression. Radioactive iodine (ROI) alternatives and interleukin-6 (IL-6) receptor antagonists could offer potential benefits and should be further explored. Longitudinal follow-ups post-COVID-19 for patients with new and pre-existing thyroid disorders can improve disease outcomes. In addition, pathophysiological research on thyroid dysfunction in COVID-19 may help develop strategies to prevent and alleviate thyroid gland abnormalities post-COVID-19.

Exploring Nausea and Vomiting: Pathophysiology, Mechanisms and Future Research Directions

Exploring Nausea and Vomiting: Pathophysiology, Mechanisms and Future Research Directions

Opposite-Direction Spatial Working Memory Biases in People With Schizophrenia and Healthy Control Participants

BackgroundPeople with schizophrenia (PSZ) show impaired accuracy in spatial working memory (sWM), which is thought to reflect abnormalities in the sustained firing of feature selective neurons that are critical for successful encoding and maintenance processes. Recent research has documented a new source of variance in the accuracy of sWM: In healthy adults, sWM representations are unconsciously biased by previous trials such that current-trial responses are attracted to previous-trial responses (serial dependence). This opens a new window to examine how schizophrenia impacts both the sustained neural firing representing the current-trial target and the longer-term synaptic plasticity that stores previous-trial information. MethodsWe examined response accuracy in a single-item sWM test with delay intervals of 0, 2, 4, or 8 seconds in 41 PSZ and 32 demographically similar healthy control participants. Our main dependent variable was the bias index, which quantifies the extent to which the current-trial responses were biased toward or away from the previous-trial target. ResultsPSZ showed opposite-direction serial dependence bias effects: Healthy control participants showed an attractive bias that increased over increasing delays whereas PSZ showed a repulsion bias that increased over delays. In PSZ, the magnitude of the repulsion bias negatively correlated with broad measures of cognitive ability and WM capacity. ConclusionsPSZ show opposite-direction effects of previous trials on WM. Such qualitatively distinct differences in performance are extremely rare in psychopathology and may index a fundamental alteration in neural processing that could serve as a valuable biomarker for pathophysiology and treatment development research.

Contrast-enhanced computed tomography for exvivo assessment of human kidneys: A proof-of-concept study.

Ex vivo perfusion of transplant-declined human organs has emerged as a promising platform to study the response of an organ to novel therapeutic strategies. However, to fully realize the capability of this platform for performing translational research in human organ pathophysiology, there is a need for robust assays to assess organ function and disease. State-of-the-art research methods rely on analyses of biopsies taken during perfusion, which both damages the organ and only provides localized information. Developing non-invasive, whole organ methods of assessment is critical to the further development of this research platform. We use ex vivo cold infusion scanning (EXCIS) with contrast-enhanced computed tomography (CT) to quantify perfusion in kidneys preserved ex vivo. EXCIS-CT computes three complementary metrics for whole organ assessment: a dynamic assessment of contrast filling, a measure of vascular network anatomical structure, and a static assessment of perfusion heterogeneity. These metrics were applied to a series of six transplant-declined human kidneys, which demonstrated a range of anatomies and perfusion. Lastly, two transplant-declined human kidneys were imaged before and after a 1-h period of ex vivo normothermic perfusion (NMP). We found variable responses to NMP, with one kidney maintaining the vascular network and hemodynamics and the other showing significant changes in vessel size and spatial perfusion profile. EXCIS-CT provides metrics that can be used to characterize whole organ perfusion and vascular function.

Proteomic Profiling in Dystonia: The Next Frontier for Pathophysiology Research and Biomarker Exploration.

Proteomic Profiling in Dystonia: The Next Frontier for Pathophysiology Research and Biomarker Exploration.

The Long-Term Cardiovascular Impact of COVID-19: Pathophysiology, Clinical Manifestations, and Management.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has resulted in a substantial global health crisis, with effects extending far beyond the acute phase of infection. This review aims to provide a comprehensive overview of the long-term cardiovascular impact of COVID-19, focusing on the pathophysiology, clinical manifestations, diagnostic approaches, management strategies, and future research directions. SARS-CoV-2 induces cardiovascular complications through mechanisms such as inflammation, endothelial dysfunction, and direct myocardial injury, leading to conditions like myocarditis, heart failure, arrhythmias, and thromboembolic events. These long-term effects, collectively called "long COVID" or post-acute sequelae of SARS-CoV-2 infection (PASC), present significant challenges for healthcare systems and patient management. Diagnostic approaches include imaging techniques and laboratory tests to identify and monitor cardiovascular complications. Management strategies emphasize a holistic approach, incorporating pharmacological treatments and lifestyle modifications. Special attention is required for vulnerable populations, including those with pre-existing cardiovascular conditions. Ongoing research is essential to understand the full spectrum of long-term cardiovascular impacts and to develop effective treatments. This review highlights the critical need for continued vigilance, multidisciplinary care, and research to address the cardiovascular sequelae of COVID-19 and improve long-term health outcomes for survivors.

Hormone receptor expression in low-grade adenosquamous carcinoma of the breast progressing to high-grade metaplastic carcinoma: A case report.

Breast low-grade adenosquamous carcinoma is an uncommon cancer that has been neglected in genetic and pathophysiological research. Consequently, medical practitioners face challenges in the effective diagnosis and treatment of this condition. We present the case of a 57-year-old Asian female patient who presented with bilateral breast masses on physical examination. Ultrasound and an MRI revealed a highly suspicious malignant mass in her right breast that was completely removed surgically. After pathological analysis, the diagnosis was low-grade adenosquamous carcinoma with local high-grade transformation, and some of the tumor components were estrogen receptor positive. The patient underwent appropriate postoperative chemotherapy and achieved a favorable outcome. During the follow-up period after surgical resection, the patient did not experience any local recurrence or distant metastasis. Owing to the rare combination of estrogen receptor positivity and high-grade progression, this patient also required adjuvant chemotherapy. This enhances the essential foundation for diagnosing and treating this rare disease, and facilitates the implementation of treatment plans.

Modern cell culture technologies: Revolutionizing neuroregeneration in neuropsychiatry

This review highlights the latest developments in current cell culture methods, including three-dimensional culture, organoids, coculture systems, microfluidics, and nanofiber scaffolds to support neuroregeneration in major neuropsychiatric illnesses. Due to the enhanced in vitro modeling of human brain structure and function, these state-of-the-art methods allow for investigations of disease processes and drug screening, and pathophysiological research on neuroregeneration has increased. We examine recent research on the relationship between these technologies and neuropsychiatric conditions such as stroke, Alzheimer’s, traumatic brain injury, and spinal cord injury. The advancements present encouraging prospects for augmenting neuroregeneration and could facilitate stem cell-based therapies for neuropsychiatric ailments that were previously untreatable.

Generation of Alzheimer's Disease Model Derived from Induced Pluripotent Stem Cells with APP Gene Mutation.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by disruptions in memory, cognition, and personality, significantly impacting morbidity and mortality rates among older adults. However, the exact pathophysiological mechanism of AD remains unknown, and effective treatment options for AD are still lacking. Human induced pluripotent stem cells (iPSC) are emerging as promising platforms for disease research, offering the ability to model the genetic mutations associated with various conditions. Patient-derived iPSCs are useful for modeling neurodegenerative and neurodevelopmental disorders. In this study, we generated AD iPSCs from peripheral blood mononuclear cells obtained from a 65-year-old patient with AD carrying the E682K mutation in the gene encoding the amyloid precursor protein. Cerebral organoids derived from AD iPSCs recapitulated the AD phenotype, exhibiting significantly increased levels of tau protein. Our analysis revealed that an iPSC disease model of AD is a valuable assessment tool for pathophysiological research and drug screening.

#1457 Human renal proximal tubule-on-a-chip model to study prevention of ischemia and reperfusion injury

Abstract Background and Aims Renal ischemia/reperfusion injury (rIRI) is characterized by restriction of blood supply followed by restoration of blood flow and re-oxygenation and is a leading cause of acute kidney injury (AKI). While animal models are useful for studying systemic manifestations of AKI, their translational relevance is limited. Human in vitro models provide valuable mechanistic insights into rIRI, but often fail to incorporate crucial aspects such as reperfusion injury. To address these limitations, this study aims to develop an advanced in vitro model to study rIRI comprising a perfused three-dimensional (3D) human renal proximal tubule-on-a-chip. Method Our proximal tubule-on-a-chip model comprises a renal proximal tubule alongside a endothelial vessel, separated by extracellular matrix. A microfluidic platform, the OrganoPlate 3-Lane 40, was used to establish the model. The resulting coculture was characterized in terms of its three-dimensional structure, protein expression, and response to nephrotoxins. Subsequently, we simulated rIRI by manipulating oxygen levels, nutrient availability, and perfusion flow settings. The potential protective effect of adenosine was evaluated in the coculture model during ischemia and reperfusion. The extent of injury was assessed through morphological evaluation, caspase 3/7 activation, and cell viability measurements. Results The combination of low oxygen, reduced glucose, and interrupted flow exerted a potent disruptive effect on the proximal tubules, which was strongly amplified upon reperfusion. Endothelial vessels were less sensitive to the ischemia–reperfusion parameters. Adenosine treatment showed a protective effect on the disruption of the epithelium and on the caspase-3/7 activation. Conclusion We successfully developed a human in vitro model to study rIRI utilizing a coculture of a proximal tubule and a blood vessel on-a-chip. This model allowed us to characterize the renoprotective effect of adenosine. The robustness of the model and assays, coupled with the platform's high throughput capabilities, position it as a promising tool for advancing pathophysiological research and facilitating the development of innovative therapeutic modalities aimed at treating rIRI and improving AKI outcomes.

Gut Microbiota and Immune System in Necrotizing Enterocolitis and Related Sepsis

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

Modular probe integrating with quantum dots based versatile platform for sensitive and label-free biomarker detection

Multiplexed analysis of biomarkers in a single sample tube is essential for accurate diagnosis and therapy of diseases. However, the existing detection platforms suffer from many drawbacks, such as low specificity, limited applicable sceneries, and complicated operation. Hence, it is highly important to develop a versatile biomarker detection platform that can be used for disease diagnosis and pathophysiological research. In this study, we provide a versatile method for detecting biomarkers using dual-loop probes and quantum dots (QDs). This approach utilizes a dual-loop probe that consists of a recognition module for identifying specific targets, a template recognition module for initiating subsequent chain replacement cycles, and a signal module for facilitating the fixation of QDs on the 96-well plate. The lower limit of detection for miRNA-21 is determined to be at the aM level. Furthermore, this design may be easily expanded to simultaneously detect several targets, such as miRNA and C-reactive protein. The experimental results demonstrated the successful construction of the versatile biomarkers detection platform, and indicated that the sensitive and versatile platform has significant potential in the areas of bio-sensing, clinical diagnostics, and environmental sample analysis.

Research progress of ferroptosis and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disorder of the gastrointestinal tract, imposing significant burdens on both society and individuals. As a new type of regulated cell death (RCD), ferroptosis is different from classic RCDs such as apoptosis and necrosis in cell morphology, biochemistry and genetics. The main molecular mechanisms of ferroptosis include dysregulation of iron metabolism, impaired antioxidant capacity, mitochondrial dysfunction, accumulation of lipid-associated super-oxides, and membrane disruption. In recent years, increasing evidence has shown that ferroptosis is involved in the pathophysiology of inflammatory bowel disease. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This article reviews the mechanism of ferroptosis in the occurrence and development of inflammatory bowel disease, in order to provide new ideas for the pathophysiological research of inflammatory bowel disease. Additionally, we discuss potential strategies for the prevention and treatment of inflammatory bowel disease by targeting ferroptosis.

White spot lesions in fixed orthodontic treatment: Etiology, pathophysiology, diagnosis, treatment, and future research perspectives.

White spot lesions (WSLs) refer to localized areas of hypo-mineralization limited to the enamel of the teeth surface, which is noticeable clinically to the naked eye on drying of the teeth. During fixed orthodontic treatment, it is very hard for the patient to maintain excellent oral hygiene as the brackets, bands, wires, elastics, and other appliances and attachments worn intra-orally provide a platform for food retention, plaque formation, and then colonization by acidogenic bacteria like Streptococcus mutans and Lactobacillus. This review aims to elaborate and focus on etiology, pathophysiology, diagnosis, treatment aspect, and future scope for research about the WSLs occurring due to fixed orthodontic treatment.

Correlation between blood inflammatory indices and carotid intima-media thickness in the middle-aged and elderly adults

ObjectivesThis study aimed to investigate the correlations between carotid intima-media thickness (IMT) and systemic immune inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte (NLR) ratio. Materials and methodsThis was a cross-sectional study enrolling a total of 582 middle-aged and elderly patients. The correlations between SII, PLR, and NLR with IMT were assessed using logistic regression models, which were subsequently incorporated into the underlying models with traditional risk factors and their predictive values for IMT. ResultsNLR exhibited a significant correlation with IMT in the simple regression analysis (β = 0.01, 95 %CI= 0.00-0.02, p < 0.05). After controlling for potential confounding variables in the multivariate analysis, the association between NLR and both Maximum IMT [β = 0.04, 95 %CI = 0.02-0.07, p = 0.0006] and Mean IMT [β = 0.05, 95 %CI = 0.02-0.07, p = 0.0001] remained statistically significant. Additionally, PLR was found to be a significant independent predictor of Maximum IMT [β = 0.04, 95 % CI =0.00-0.07, p = 0.0242] and Mean IMT [β = 0.04, 95 % CI = 0.01-0.07, p = 0.0061]. Similarly, SII was identified as an independent predictor of Maximum IMT [β = 1.87, 95 % CI =1.24, p = 0.0003]. The study found a significant positive correlation between Maximum IMT and the levels NLR, PLR, and SII. Specifically, in the Maximum IMT group, higher quartiles of NLR, PLR, and SII were associated with increased odds ratios (OR) for elevated IMT levels, with statistically significant results for NLR (Q4vsQ1: OR 3.87, 95 % CI 1.81-8.29), PLR (Q4vsQ1: OR 2.84, 95 % CI 1.36-5.95), and SII (Q4vsQ1: OR 2.64, 95 % CI 1.30-5.37). Finally, the inclusion of NLR, PLR, and NLR+PLR+SII in the initial model with traditional risk factors resulted in a marginal improvement in the predictive ability for Maximum IMT, as evidenced by the net reclassification index (p < 0.05). ConclusionsThis study discovered a positive correlation between SII, PLR, NLR, and IMT, which are likely to emerge as new predictors for IMT thickening. These findings lay a theoretical reference for future predictive research and pathophysiological research on carotid intima-media thickening.

The role of tubular cells in the pathogenesis of Fabry nephropathy.

The pathophysiology of Fabry nephropathy (FN) is induced by galactosidase A deficiency with a chronic exposure of glycolipids to every lineage of renal cells. Tissue damage is attributed to the activation of molecular pathways, resulting in tissue fibrosis and chronic kidney disease. Podocytes have been the primary focus in clinical pathophysiological research because of the striking accumulation of large glycolipid deposits observable in histology. Yet, the tubular interstitium makes up a large portion of the whole organ, and therefore, its role must be further considered in pathogenic processes. In this review, we would like to propose Fabry tubulopathy and its ensuing functional effects as the first pathological signs and contributing factors to the development of FN. We will summarize and discuss the current literature regarding the role of tubular cells in Fabry kidney pathophysiology. Starting from clinical and histological evidence, we will highlight the data from animal models and cell cultures outlining the pathophysiological pathways associated with tubular interstitial injury causing renal fibrosis in Fabry nephropathy.

Ischemic stroke pathophysiology: A bibliometric and visualization analysis from 1990 to 2022

BackgroundPathophysiology plays a significant role in the scientific study of ischemic stroke, and has attracted increasing interest from researchers in the field. However, a comprehensive bibliometric analysis is lacking in this field. The purpose of this study is to identify the current research status and hotspots of ischemic stroke pathophysiology from a bibliometric perspective. MethodsThe Web of Science Core Collection database was searched for articles published from 1990 to 2022. CiteSpace, VOSviewer, and R package “bibliometrix” software were used to analyze countries/regions, institutions, journals, authors, papers, and keywords to predict the latest trends in ischemic stroke pathophysiology research. ResultsThis analysis collected 7578 records of ischemic stroke pathophysiology. China and America emerged as the leading countries in this field, with Harvard University being the most active institution. Among journals and authors in this field, journal Stroke and author Gregory YH Lip published the most papers, while Nature Medicine was the journal with the highest citation per article. Keywords and co-citation clusters were closely related to “central nervous system”, “mechanisms”, “biochemistry & molecular biology” and “radiology, nuclear medicine & medical imaging”, while other related fields, such as peripheral organs damage induced by the central nervous system and rehabilitation after ischemic stroke, require further research efforts. ConclusionThis is the first bibliometric study that comprehensively mapped out the knowledge structure and development trends of ischemic stroke pathophysiology in recent 32 years, which may provide a reference for scholars to explore ischemic stroke pathophysiology.

Tinnitus: Clinical Insights in Its Pathophysiology-A Perspective

Tinnitus, the perception of sound without a corresponding external sound source, and tinnitus disorder, which is tinnitus with associated suffering, present a multifaceted clinical challenge due to its heterogeneity and its incompletely understood pathophysiology and especially due to the limited therapeutic options. In this narrative review, we give an overview on various clinical aspects of tinnitus including its heterogeneity, contributing factors, comorbidities and therapeutic pathways with a specific emphasis on the implications for its pathophysiology and future research directions. Tinnitus exhibits high perceptual variability between affected individuals (heterogeneity) and within affected individuals (temporal variability). Hearing loss emerges as predominant risk factor and the perceived pitch corresponds to areas of hearing loss, supporting the compensatory response theory. Whereas most people who have tinnitus can live a normal life, in 10–20% tinnitus interferes severely with quality of life. These patients suffer frequently from comorbidities such as anxiety, depression or insomnia, acting as both risk factors and consequences. Accordingly, neuroimaging studies demonstrate shared brain networks between tinnitus and stress-related disorders shedding light on the intricate interplay of mental health and tinnitus. The challenge lies in deciphering causative relationships and shared pathophysiological mechanisms. Stress, external sounds, time of day, head movements, distraction, and sleep quality can impact tinnitus perception. Understanding these factors provides insights into the interplay with autonomic, sensory, motor, and cognitive processes. Counselling and cognitive-behavioural therapy demonstrate efficacy in reducing suffering, supporting the involvement of stress and anxiety-related networks. Hearing improvement, especially through cochlear implants, reduces tinnitus and thus indirectly validates the compensatory nature of tinnitus. Brain stimulation techniques can modulate the suffering of tinnitus, presumably by alteration of stress-related brain networks. Continued research is crucial for unravelling the complexities of tinnitus. Progress in management hinges on decoding diverse manifestations, identifying treatment-responsive subtypes, and advancing targeted therapeutic approaches.

PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.

We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3' splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.