Understanding the Role of Filamentous Actin in Food Quality: From Structure to Application.

Actin, a multifunctional protein highly expressed in eukaryotes, is widely distributed throughout cells and serves as a crucial component of the cytoskeleton. Its presence is integral to maintaining cell morphology and participating in various biological processes. As an irreplaceable component of myofibrillar proteins, actin, including G-actin and F-actin, is highly related to food quality. Up to now, purification of actin at a moderate level remains to be overcome. In this paper, we have reviewed the structures and functions of actin, the methods to obtain actin, and the relationships between actin and food texture, color, and flavor. Moreover, actin finds applications in diverse fields such as food safety, bioengineering, and nanomaterials. Developing an actin preparation method at the industrial level will help promote its further applications in food science, nutrition, and safety.

HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy.

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.

Species -shared and -unique gyral peaks on human and macaque brains.

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.

The transcription factor BMI1 increases hypoxic signaling in oral cavity epithelia.

The tongue epithelium is maintained by a proliferative basal layer. This layer contains long-lived stem cells (SCs), which produce progeny cells that move up to the surface as they differentiate. B-lymphoma Mo-MLV insertion region 1 (BMI1), a protein in mammalian Polycomb Repressive Complex 1 (PRC1) and a biomarker of oral squamous cell carcinoma, is expressed in almost all basal epithelial SCs of the tongue, and single, Bmi1-labelled SCs give rise to cells in all epithelial layers. We previously developed a transgenic mouse model (KrTB) containing a doxycycline- (dox) controlled, Tet-responsive element system to selectively overexpress Bmi1 in the tongue basal epithelial SCs. Here, we used this model to assess BMI1 actions in tongue epithelia. Genome-wide transcriptomics revealed increased levels of transcripts involved in the cellular response to hypoxia in Bmi1-overexpressing (KrTB+DOX) oral epithelia even though these mice were not subjected to hypoxia conditions. Ectopic Bmi1 expression in tongue epithelia increased the levels of hypoxia inducible factor-1 alpha (HIF1α) and HIF1α targets linked to metabolic reprogramming during hypoxia. We used chromatin immunoprecipitation (ChIP) to demonstrate that Bmi1 associates with the promoters of HIF1A and HIF1A-activator RELA (p65) in tongue epithelia. We also detected increased SC proliferation and oxidative stress in Bmi1-overexpressing tongue epithelia. Finally, using a human oral keratinocyte line (OKF6-TERT1R), we showed that ectopic BMI1 overexpression decreases the oxygen consumption rate while increasing the extracellular acidification rate, indicative of elevated glycolysis. Thus, our data demonstrate that high BMI1 expression drives hypoxic signaling, including metabolic reprogramming, in normal oral cavity epithelia.

Metal-Binding Protein TaGlo1 Improves Fungal Resistance to Arsenite (AsIII) and Methylarsenite (MAsIII) in Paddy Soil.

Trivalent arsenicals such as arsenite (AsIII) and methylarsenite (MAsIII) are thought to be ubiquitous in flooded paddy soils and have higher toxicity than pentavalent forms. Fungi are widely prevalent in the rice rhizosphere, and the latter is considered a hotspot for As uptake. However, few studies have focused on alleviating As toxicity in paddy soils using fungi. In this study, we investigated the mechanism by which the protein TaGlo1, derived from the As-resistant fungal strain Trichoderma asperellum SM-12F1, mitigates AsIII and MAsIII toxicity in paddy soils. Taglo1 gene expression in Escherichia coli BL21 conferred strong resistance to AsIII and MAsIII, while purified TaGlo1 showed a high affinity for AsIII and MAsIII. Three cysteine residues (Cys13, Cys18, and Cys71) play crucial roles in binding with AsIII, while only two (Cys13 and Cys18) play crucial roles for MAsIII binding. TaGlo1 had a stronger binding strength for MAsIII than AsIII. Importantly, up to 90.2% of the homologous TaGlo1 proteins originate from fungi by GenBank searching. In the rhizospheres of 14 Chinese paddy soils, Taglo1 was widely distributed and its gene abundance increased with porewater As. This study highlights the potential of fungi to mitigate As toxicity and availability in the soil-rice continuum and suggests future microbial strategies for bioremediation.

Obesity and septic patient outcomes: Shaping the puzzle through age and sex perspectives.

BACKGROUND & AIMS: While obesity has been reported as a protective factor in septic patients, little is known about the potential modifying effects of age and sex. The objective of this study is to investigate age and sex-specific associations between obesity and the prognosis of septic patients. METHODS: A retrospective analysis was conducted on a cohort of 15,464 septic patients, categorized by body mass index (BMI) into four groups: underweight (<18.5 kg/m2, n = 483), normal (18.5-24.9 kg/m2, n = 4344), overweight (25-29.9 kg/m2, n = 4949) and obese (≥30 kg/m2, n = 5688). Multivariable logistic regression and inverse probability weighting were employed to robustly confirm the protective effect of a higher BMI on 28-day mortality, with normal weight serving as the reference category. Subgroup analyses based on age (young: 18-39, middle-aged: 40-64 and elderly: ≥65) and sex were performed. RESULTS: The findings demonstrate that high BMI independently confers a protective effect against 28-day mortality in septic patients. However, the relationship between BMI and 28-day mortality exhibits a non-linear trend, with a BMI of 34.5 kg/m2 displaying the lowest odds ratio. Notably, the survival benefits associated with a high BMI were not observed in the young group. Moreover, being underweight emerges as an independent risk factor for middle-aged and elderly female patients, while in males it is only a risk factor in the elderly group. Interestingly, being overweight and obese were identified as independent protective factors in middle-aged and elderly male patients, but not in females. CONCLUSIONS: The effect of BMI on mortality in septic patients varies according to age and sex. Elderly individuals with sepsis may derive more prognostic benefits from obesity.

Hierarchical functional differences between gyri and sulci at different scales.

Gyri and sulci are 2 fundamental cortical folding patterns of the human brain. Recent studies have suggested that gyri and sulci may play different functional roles given their structural and functional heterogeneity. However, our understanding of the functional differences between gyri and sulci remains limited due to several factors. Firstly, previous studies have typically focused on either the spatial or temporal domain, neglecting the inherently spatiotemporal nature of brain functions. Secondly, analyses have often been restricted to either local or global scales, leaving the question of hierarchical functional differences unresolved. Lastly, there has been a lack of appropriate analytical tools for interpreting the hierarchical spatiotemporal features that could provide insights into these differences. To overcome these limitations, in this paper, we proposed a novel hierarchical interpretable autoencoder (HIAE) to explore the hierarchical functional difference between gyri and sulci. Central to our approach is its capability to extract hierarchical features via a deep convolutional autoencoder and then to map these features into an embedding vector using a carefully designed feature interpreter. This process transforms the features into interpretable spatiotemporal patterns, which are pivotal in investigating the functional disparities between gyri and sulci. We evaluate the proposed framework on Human Connectome Project task functional magnetic resonance imaging dataset. The experiments demonstrate that the HIAE model can effectively extract and interpret hierarchical spatiotemporal features that are neuroscientifically meaningful. The analyses based on the interpreted features suggest that gyri are more globally activated, whereas sulci are more locally activated, demonstrating a distinct transition in activation patterns as the scale shifts from local to global. Overall, our study provides novel insights into the brain's anatomy-function relationship.

Polycomb repressive complex 1 modulates granulosa cell proliferation in early folliculogenesis to support female reproduction.

Rationale: Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI. Methods: We used whole genome sequencing (WGS), conditional knockout mouse models combined with laser capture microdissection (LCM), and RNA/ChIP sequencing to analyze the crucial roles of polycomb repressive complex 1 (PRC1) in clinical POI and mammalian folliculogenesis. Results: A deletion mutation of MEL18, the key component of PRC1, was identified in a 17-year-old patient. However, deleting Mel18 in granulosa cells (GCs) did not induce infertility until its homolog, Bmi1, was deleted simultaneously. Double deficiency of BMI1/MEL18 eliminated PRC1 catalytic activity, upregulating cyclin-dependent kinase inhibitors (CDKIs) and thus blocking GC proliferation during primary-to-secondary follicle transition. This defect led to damaged intercellular crosstalk, eventually resulting in gonadotropin response failure and infertility. Conclusions: Our findings highlighted the pivotal role of PRC1 as an epigenetic regulator of gene transcription networks in GC proliferation during early folliculogenesis. In the future, a better understanding of molecular details of PRC1 structural and functional abnormalities may contribute to POI diagnosis and therapeutic options.

LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells.

In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

Structural Insights into the Reaction between Hydrogen Peroxide and Di-iron Complexes at the Ferroxidase Center of Ferritin.

The Fe(II) oxidation mechanism in the ferroxidase center of heavy chain ferritin has been studied extensively. However, the actual production of H2O2 was found to be substantially lower than expected at low flux of Fe(II) to ferritin subunits. Here, we demonstrated that H2O2 could interact with the di-iron nuclear center, leading to the production of hydroxyl radicals and oxygen. Two reaction intermediates were captured in the ferroxidase center by using the time-lapse crystallographic techniques in a shellfish ferritin. The crystal structures revealed the binding of H2O2 as a µ -1,2-peroxo-diferric species and the binding of O2 to the diferric structure. This investigation sheds light on the reaction between the di-iron nuclear center and H2O2 and provides insights for the exploitation of metalloenzymes.

SARS-CoV-2 infection causes dopaminergic neuron senescence.

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

Novel Local-Chiral Metamaterial: Effective Modulation of Amplitude & Phase for Wideband Polarization-Insensitive Absorption.

Metamaterial has received widespread research in the fields of electromagnetic stealth due to its characteristics of strong resonance and flexible designability. However, a lack of a comprehensive understanding of the internal physical mechanism still imposes certain limitations on broadband absorption designs. Hence, this work proposes a new strategy for the broadening of the working frequency band of metamaterial absorbers by constructing local-chiral features to regulate the amplitude and phase information. The absorber consists of staggered cut-wire metal patterns with lumped resistors placed at the center position determined by characteristic mode analysis. Combining the modal significance, equivalent circuit, surface current, electric field distribution, and symmetry model theory, the working mechanism for wideband absorption performance has been analyzed in detail. The experimental results are in good agreement with the simulation results; the absorption rate exceeds 82% in the frequency range of 4.5-11.7 GHz and surpasses about 90% in the frequency range of 4.7-10.8 GHz under transverse electric (TE) or transverse-magnetic (TM) polarizations. Compared to the case without chiral features, the proposed design can achieve a 28% increase in operating bandwidth. The proposed design method is applicable for the optimization of various typical dipole-type metamaterial absorbers and provides a novel strategy for future wideband metamaterial absorption.

Brain Structural Connectivity Guided Vision Transformers for Identification of Functional Connectivity Characteristics in Preterm Neonates.

Preterm birth is the leading cause of death in children under five years old, and is associated with a wide sequence of complications in both short and long term. In view of rapid neurodevelopment during the neonatal period, preterm neonates may exhibit considerable functional alterations compared to term ones. However, the identified functional alterations in previous studies merely achieve moderate classification performance, while more accurate functional characteristics with satisfying discrimination ability for better diagnosis and therapeutic treatment is underexplored. To address this problem, we propose a novel brain structural connectivity (SC) guided Vision Transformer (SCG-ViT) to identify functional connectivity (FC) differences among three neonatal groups: preterm, preterm with early postnatal experience, and term. Particularly, inspired by the neuroscience-derived information, a novel patch token of SC/FC matrix is defined, and the SC matrix is then adopted as an effective mask into the ViT model to screen out input FC patch embeddings with weaker SC, and to focus on stronger ones for better classification and identification of FC differences among the three groups. The experimental results on multi-modal MRI data of 437 neonatal brains from publicly released Developing Human Connectome Project (dHCP) demonstrate that SCG-ViT achieves superior classification ability compared to baseline models, and successfully identifies holistically different FC patterns among the three groups. Moreover, these different FCs are significantly correlated with the differential gene expressions of the three groups. In summary, SCG-ViT provides a powerfully brain-guided pipeline of adopting large-scale and data-intensive deep learning models for medical imaging-based diagnosis.

A Unified and Biologically Plausible Relational Graph Representation of Vision Transformers.

Vision transformer (ViT) and its variants have achieved remarkable success in various tasks. The key characteristic of these ViT models is to adopt different aggregation strategies of spatial patch information within the artificial neural networks (ANNs). However, there is still a key lack of unified representation of different ViT architectures for systematic understanding and assessment of model representation performance. Moreover, how those well-performing ViT ANNs are similar to real biological neural networks (BNNs) is largely unexplored. To answer these fundamental questions, we, for the first time, propose a unified and biologically plausible relational graph representation of ViT models. Specifically, the proposed relational graph representation consists of two key subgraphs: an aggregation graph and an affine graph. The former considers ViT tokens as nodes and describes their spatial interaction, while the latter regards network channels as nodes and reflects the information communication between channels. Using this unified relational graph representation, we found that: 1) model performance was closely related to graph measures; 2) the proposed relational graph representation of ViT has high similarity with real BNNs; and 3) there was a further improvement in model performance when training with a superior model to constrain the aggregation graph.

Synbiotic Combination between Lactobacillus paracasei VL8 and Mannan-Oligosaccharide Repairs the Intestinal Barrier in the Dextran Sulfate Sodium-Induced Colitis Model by Regulating the Intestinal Stem Cell Niche.

Previously, Lactobacillus paracasei VL8, a lactobacillus strain isolated from the traditional Finnish fermented dairy product Viili, demonstrated immunomodulatory and antibacterial effects. The prebiotic mannan-oligosaccharide (MOS) further promoted its antibacterial activity and growth performance, holding promise for maintaining intestinal health. However, this has not been verified in vivo. In this study, we elucidated the process by which L. paracasei VL8 and its synbiotc combination (SYN) with MOS repair the intestinal barrier function in dextran sodium sulfate (DSS)-induced colitis mice. SYN surpasses VL8 or MOS alone in restoring goblet cells and improving the tight junction structure. Omics analysis on gut microbiota reveals SYN's ability to restore Lactobacillus spp. abundance and promote tryptophan metabolism. SYN intervention also inhibits the DSS-induced hyperactivation of the Wnt/ß-catenin pathway. Tryptophan metabolites from Lactobacillus induce intestinal organoid differentiation. Co-housing experiments confirm microbiota transferability, replicating intestinal barrier repair. In conclusion, our study highlights the potential therapeutic efficacy of the synbiotic combination of Lactobacillus paracasei VL8 and MOS in restoring the damaged intestinal barrier and offers new insights into the complex crosstalk between the gut microbiota and intestinal stem cells.

Species -Shared and -Unique Gyral Peaks on Human and Macaque Brains.

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, we defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. In this study, we identified shared and unique gyral peaks in human and macaque, and investigated the similarities and differences in the spatial distribution, anatomical morphology, and functional connectivity of them.

Interactions between paramyosin and actin greatly improve their thermostability and gel properties.

BACKGROUND: Myofibrillar proteins, the main contributors to the quality of meat products, are the main structural protein component of muscle and have functional properties such as the formation of a 3D protein gel network and water binding. The susceptibility of meat-derived proteins to heat-induced aggregation is the functional constraint that hinders their applications in industry, and so establishing an effective but simple method to improve their thermostability of the proteins is of great importance. RESULTS: In the present study, we describe an easy approach to perform high colloidal thermostability of both paramyosin and actin by mixing them at low ionic strength. The improvement in thermal stability was found to be derived from intermolecular interactions between these two different proteins through non-covalent binding with each other. Consequently, such interactions protected each of them from thermal-induced degradation compared to individual components. Notably, this binary native protein mixture rather than single paramyosin or actin component has the ability to form protein hydrogels with a shear-thinning and reversible sol-gel transformation behavior, which is markedly different from most of reported heat-induced, denatured protein hydrogels. CONCLUSION: The present study not only presents a facile and effective strategy for improvement of the thermal stability and gel properties of a binary paramyosin and actin mixture, but also enhances our understanding of how mutual interactions of protein components affect their physicochemical and functional properties. © 2023 Society of Chemical Industry.

Regularity and variability of functional brain connectivity characteristics between gyri and sulci under naturalistic stimulus.

The human cerebral cortex is folded into two fundamentally anatomical units: gyri and sulci. Previous studies have demonstrated the genetical, structural, and functional differences between gyri and sulci, providing a unique perspective for revealing the relationship among brain function, cognition, and behavior. While previous studies mainly focus on the functional differences between gyri and sulci under resting or task-evoked state, such characteristics under naturalistic stimulus (NS) which reflects real-world dynamic environments are largely unknown. To address this question, this study systematically investigates spatio-temporal functional connectivity (FC) characteristics between gyri and sulci under NS using a spatio-temporal graph convolutional network model. Based on the public Human Connectome Project dataset of 174 subjects with four different runs of both movie-watching NS and resting state 7T functional MRI data, we successfully identify unique FC features under NS, which are mainly involved in visual, auditory, emotional and cognitive control, and achieve high discriminative accuracy 93.06 % to resting state. Moreover, gyral regions as well as gyro-gyral connections consistently participate more as functional information exchange hubs than sulcal ones among these networks. This study provides novel insights into the functional brain mechanism under NS and lays a solid foundation for accurately mapping the brain anatomy-function relationship.

High-efficiency antibacterial calcium alginate/lysozyme/AgNPs composite sponge for wound healing.

Infection poses a significant barrier to effective wound repair, leading to increased inflammatory responses that ultimately result in incomplete and prolonged wound healing. To address this challenge, numerous antibacterial ingredients have been incorporated into dressings to inhibit wound infection. Our previous work demonstrated that lysozyme/silver nanoparticles (LYZ/AgNPs) complexes, prepared using an eco-friendly one-step aqueous method, exhibited excellent antibacterial efficacy with favorable biosafety. To further explore its potential application in advancing wound healing, calcium alginate (CA) with good porosity, water absorption, and water retention capacities was formulated with LYZ/AgNPs to prepare composite sponge (CA/LYZ/AgNPs). As expected, in vivo experiments involving full-thickness skin wound and scald wound healing experiments demonstrated that CA-LYZ-AgNPs composite sponges with excellent biocompatibility exhibited remarkable antibacterial activity against gram-positive bacteria, gram-negative bacteria and fungi, and outperformed the wound healing process efficacy of other commercially available AgNPs-loaded wound dressings. In summary, this work introduces a CA/LYZ/AgNPs sponge featuring exceptional antibacterial efficacy and biocompatibility, thus holding promising potential in wound care applications.

A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS.

KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.