Association between vitamin B2 intake and prostate-specific antigen in American men: 2003-2010 National Health and Nutrition Examination Survey.

BACKGROUND: Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database. METHODS: From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels. RESULTS: The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration. CONCLUSIONS: Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.

The Anti-Photoaging Activity of Peptides from Pinctada martensii Meat.

Long-term exposure to ultraviolet-B (UVB) can cause photoaging. Peptides from Pinctada martensii meat have been shown to have anti-photoaging activities, but their mechanism of action is rarely studied. In this study, Pinctada martensii meat hydrolysates (PME) were prepared by digestive enzymes and then separated by ultrafiltration and Sephadex G-25 gel filtration chromatography to obtain a purified fraction (G2). The fraction G2 was identified by ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), and peptide sequences were synthesized by solid-phase synthesis. The mechanism of anti-photoaging activities was investigated using a human immortalised epidermal (HaCaT) cell model. Results showed that peptides from Pinctada martensii meat increased UVB-induced cell viability and reduced the contents of interstitial collagenase (MMP-1) and matrix lysing enzyme (MMP-3) in HaCaT cells. Furthermore, the fraction of G2 significantly downregulated the expression of p38, EKR, JNK, MMP-1, and MMP-3 in HaCaT cells. The peptide sequences Phe-His (FH), Ala-Leu (AL), Met-Tyr (MY), Ala-Gly-Phe (AGF), and Ile-Tyr-Pro (IYP) were identified and synthesized. Besides, FH reduced the contents of MMP-1 and MMP-3 in HaCaT cells, combining them effectively in molecular docking analysis. Thus, peptides from Pinctada martensii meat showed anti-photoaging activities and might have the potential to be used as an anti-photoaging agent in functional foods.

A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation.

Targeted protein degradation (TPD) has risen as a promising therapeutic modality. Leveraging the catalytic nature of the ubiquitin-proteasome enzymatic machinery, TPD exhibits higher potency to eliminate disease-causing target proteins such as oncogenic transcription factors that may otherwise be difficult to abrogate by conventional inhibitors. However, there are challenges that remain. Currently, nearly all degraders engage CUL4CRBN or CUL2VHL as the E3 ligase for target ubiquitination. While their immediate efficacies are evident, the narrowed E3 ligase options make TPD vulnerable to potential drug resistance. In addition, E3 ligases show differential tissue expression and have intrinsic limitations in accessing varying types of disease-relevant targets. As the success of TPD is closely associated with the ability of E3 ligases to efficiently polyubiquitinate the target of interest, the long-term outlook of TPD drug development will depend on whether E3 ligases such as CUL4CRBN and CUL2VHL are accessible to the targets of interest. To overcome these potential caveats, a broad collection of actionable E3 ligases is required. Here, we designed a macrocyclic degrader engaging CUL3KLHL20 for targeting BET proteins and validated CUL3KLHL20 as an E3 ligase system suitable for TPD. This work thus contributes to the expansion of usable E3 ligases for potential drug development.

TNFα activation and TGFß blockage act synergistically for smooth muscle cell calcification in patients with venous thrombosis via TGFß/ERK pathway.

Venous calcification has been observed in post-thrombotic syndrome (PTS) patients; yet, the cell types and possible mechanisms regulating this process are still unclear. We evaluated the calcium deposition within the venous wall, the cell type involved in the calcified remodelling of the venous wall after thrombosis and explored possible mechanisms in vitro. Calcium deposition was found in human specimens of superficial thrombotic veins and was co-localized with VSMCs markers αSMA and TAGLN (also known as SM22α). Besides, the expression of osteogenesis-related genes was dramatically changed in superficial thrombotic veins. Moreover, the inhibition of the TGFß signalling pathway after TNFα treatment effectively induced the expression of osteogenic phenotype markers, the calcium salt deposits and the obvious phosphorylation of ERK1/2 and JNK2 in the VSMCs calcification model. Supplementing TGFß2 or blocking the activation of the ERK/MAPK signalling pathway prevented the transformation of VSMCs into osteoblast-like cells in vitro. Taken together, VSMCs have an important role in venous calcification after thrombosis. Supplementing TGFß2 or inhibiting the ERK/MAPK signalling pathway can reduce the appearance of VSMCs osteogenic phenotype. Our findings may present a novel therapeutic approach to prevent of vascular calcification after venous thrombosis.

Cytokine storm and targeted therapy in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The central pathogenesis is an explosive cytokine storm characterized by a significant increase in proinflammatory cytokines, including IL-1ß, IL-6, IL-18, IFN-γ, and TNF-α. Meanwhile, negative regulatory factors, such as IL-10 and TGF-ß, are also related to the production of HLH. Exploring the specific mechanism of cytokine storms could provide ideas regarding targeted therapy, which could be helpful for early treatment to reduce the mortality of HLH. Although some research has focused on the advantages of targeted therapies, there is still a lack of a comprehensive discourse. This article attempts to summarize the mechanisms of action of various cytokines and provide a therapeutic overview of the current targeted therapies for HLH.

PDGF-BB-derived supramolecular hydrogel for promoting skin wound healing.

Chronic wounds represent a major challenge to the present healthcare system. In recent decades, many topical therapies have been investigated for the treatment of chronic wounds, including different types of wound dressings, antimicrobial agents, and cell therapy. Platelet-derived growth factor (PDGF) plays an important role in wound healing and has been approved for treatment of wounds related to diabetes mellitus. However, the high cost and short retention time of PDGF protein have limited its wide application. To overcome this challenge, we designed a PDGF-mimicking peptide by connecting PDGF epitope VRKIEIVRKK and self-assembling motif derived from ß-amyloid peptide. The resultant peptide can self-assemble into a fibril-rich network and leads to supramolecular hydrogelation with good stability. The hydrophilic epitope can be exposed on the surface of nanofibrils, which might contribute to the binding and activation of PDGF receptors. The forming hydrogel is able to induce the growth and migration of vascular endothelial cells and promote the formation of vascular branches. In the full-thickness skin wounds of healthy mice, after the application of the hydrogel, the density of neovascularization marked by CD31 was greater than that in the control group on Day 3. Larger collagen deposition and a thicker epidermis were observed on Day 12. These results demonstrate that the hydrogel can stimulate collagen deposition and angiogenesis, enhance skin regeneration, and show an excellent therapeutic effect. Taken together, this work not only provides new insight into the design of bioactive peptides but also offers a promising biomaterial for wound healing.

Effects of Aerobic Exercise on Rats with Hyperandrogenic Polycystic Ovarian Syndrome.

Hyperandrogenism is a key pathologic characteristic of polycystic ovarian syndrome (PCOS), and exercise can alleviate the accompanying inflammation and decrease the high androgen levels, but the mechanism is still unclear, so the purpose of this study is to explore the pathophysiologic characteristics of hyperandrogenic PCOS and the mechanism underlying its amelioration with aerobic exercise. Thirty-two female rats were randomly allocated to a normal control group (NC, n = 8), exercise control group (EC, n = 8), PCOS group (PC, n = 8), and PCOS plus exercise group (PE, n = 8). The PC and PE groups were injected with a dehydroepiandrosterone (DHEA) solution to induce the hyperandrogenic PCOS rat model. The EC and PE groups underwent a Masashi swimming protocol (120 min per session, 6 days/week, for 15 days). Results indicated that the concentrations of leptin (LP) in the EC group were significantly lower than those in the NC group (p < 0.05). Compared with the NC group, the levels of testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), LP, anti-Müllerian hormone (AMH), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and free fatty acids (FFA) were all significantly augmented in the PC group (all p < 0.05). In addition, compared with the NC group, the levels of adiponectin (ADP) were significantly decreased (p < 0.05), and the expression of aromatase cytochrome P450 (P450arom) in ovarian tissue was significantly elevated in the PC group (p < 0.05). The levels of T, FSH, LP, and FFA were also significantly increased in the PE group (p < 0.05). Compared with the PC group, the levels of T and LP in the PE group were significantly diminished (p < 0.05), and the levels of ADP were significantly increased in the PE group (p < 0.05). T was positively correlated with E2, FSH, AMH, LP, TNF-α, IL-6, and FFA levels, while ADP was negatively correlated with LP and E2. These results showed that hyperandrogenism, chronic low-grade inflammation, and leptin resistance may interact to influence the occurrence and development of PCOS. Aerobic exercise can alleviate the internal inflammation by relieving leptin resistance and may mitigate the sex hormone disorder and hyperandrogenism in rats with PCOS by affecting the hypothalamic-pituitary-ovarian axis.

Tanshinone Inhibits NSCLC by Downregulating AURKA Through Let-7a-5p.

Lung cancer is the most deadly malignancy in the last decade, accounting for about 1.6 million deaths every year globally. Tanshinone is the constituent of Salvia miltiorrhiza; it has been found that they influence tumorigenesis. However, the role of tanshinones on lung cancer is still not clear. Let-7a-5p, a short non-coding RNA, is regarded as a suppressor gene in tumorigenesis. Herein, we verified that let-7a-5p is significantly downregulated in non-small-cell lung cancer (NSCLC) tissues and cell lines. Tanshinone suppressed the expression of aurora kinase A (AURKA), inhibited cell proliferation, and arrested cell cycle progression. Our results showed that tanshinones suppressed NSCLC by upregulating the expressions of let-7a-5p via directly targeting AURKA. Besides, the data reveal that the knockdown of AURKA can also inhibit cell proliferation, arrest cell cycle, and promote cell apoptosis. Furthermore, this study demonstrates that AURKA was negatively correlated with let-7a-5p in NSCLC patient tissues. Taken together, our findings suggest that tanshinone inhibits NSCLC by downregulating AURKA through let-7a-5p. Tanshinones and let-7a-5p have the potential to be candidates for drug development of NSCLC. In conclusion, this study revealed that tanshinones with miRNA linking lead to partial mechanism in NSCLC.

The MiR-17-92 Gene Cluster is a Blood-Based Marker for Cancer Detection in Non-Small-Cell Lung Cancer.

BACKGROUND: Lung cancer is one of the most malignant cancers threatening human health. The miR-17-92 gene cluster is a highly conserved oncogene cluster encoding 6 miRNAs: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a and miR-92a. This study explored whether these miRNAs can be used as diagnostic markers for non-small-cell lung cancer (NSCLC). METHODS: Serum samples were collected from healthy subjects (n = 23) and NSCLC patients at various stages (n = 74). Serum RNA was extracted by the TRIzol-glycogen method, and cDNA libraries were constructed by reverse transcription. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression levels of the 6 miRNAs. RESULTS: The expression levels of the 6 miRNAs varied in different stages of NSCLC. Thus, 2 receiver operating characteristic (ROC) curves, that is, normal subjects and stage I-III patients and normal subjects and stage IV patients, of each miRNA were established to determine the interval of normal ΔCt values. The 2 areas under the curve (AUCs) of each miRNA were investigated (miR-17: 0.8097 and 1.000; miR-18a: 0.7388 and 0.9907; miR-19a/19b: 0.8451 and 0.5104; miR-20a: 0.8975 and 1.000; miR-92a: 0.8097 and 0.8342). In addition, a high positive correlation was discovered between miR-17 and miR-20a expression. Combining these 2 miRNAs can improve the screening effect of NSCLC. CONCLUSION: The miR-17-92 gene cluster can likely serve as a diagnostic marker in NSCLC.

Downregulation of oncogenic gene TGFßR2 by miRNA-107 suppresses non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases with a low 5-year survival rate. MicroRNA may be targeted in the clinical treatment of the disease. In this study, miR-107 showed low expression in NSCLC serum samples, and it could suppress cell proliferation, migration and arrest cell cycle in NSCLC cell lines. Results revealed that miR-107 could inhibit the expression of transforming growth factor ß receptor 2 (TGFßR2) via targeting TGFßR2. Downregulation of TGFßR2 also suppressed cell proliferation, migration and cell cycle in NSCLC cell lines. Our data suggested that miR-107 could inhibit the progression of NSCLC by targeting TGFßR2.

Inflammatory markers and treatment outcome in treatment resistant depression: A systematic review.

BACKGROUND: A substantial percentage of depressed patients do not respond satisfactorily to conventional antidepressant treatment. This treatment resistant depression (TRD) may be partly related to inflammatory processes in the central nervous system. Accordingly, peripheral inflammatory markers might serve to predict treatment response with novel but still experimental forms of antidepressant treatment. METHODS: A literature search on treatment of TRD and inflammatory markers was performed using the PubMed/Medline database on November 8th 2018, and 95 articles were retrieved initially, which were subsequently screened and selected only when the inclusion and exclusion criteria were met. RESULTS: Ten studies were recruited. In five studies higher baseline interleukin-6 (IL-6) or C-reactive protein (CRP)/high-sensitivity-CRP (hsCRP) in blood predicted better response to medication with anti-inflammatory characteristics, such as ketamine and infliximab. One study found that higher IL-6 predicted worse response to antidepressant treatment in patients with TRD. No evidence was found for the predictive value of other inflammatory markers (e.g., Tumor Necrosis Factor-α, Interferon-γ). LIMITATIONS: The number of available studies was limited; included studies showed considerable methodological variation and used different definitions for TRD. CONCLUSION: The inflammatory markers IL-6 and CRP/hsCRP could hold promise as markers for the prediction of treatment response in TRD. Clearly, this field of research is still far from mature but it could pave the way for novel and efficacious treatments for at least the inflammatory type of TRD with more well-designed studies and more convincing results.

Rational Design of TiO-TiO2 Heterostructure/Polypyrrole as a Multifunctional Sulfur Host for Advanced Lithium-Sulfur Batteries.

Despite outstanding theoretical energy density (2600 Wh kg-1) and low cost of lithium-sulfur (Li-S) batteries, their practical application is seriously hindered by inferior cycle performance and low Coulombic efficiency due to the "shuttle effect" of lithium polysulfides (LiPSs). Herein, we proposed a strategy that combines TiO-TiO2 heterostructure materials (H-TiO x, x = 1, 2) and conductive polypyrrole (PPy) to form a multifunctional sulfur host. Initially, the TiO-TiO2 heterostructure can enhance the redox reaction kinetics of sulfur species and improve the conductivity of sulfur cathode together with the PPy coating layer. Moreover, the defect-abundant H-TiO x matrices can trap LiPSs by the formation of Ti-S bond via the Lewis acid-base interaction. Furthermore, the PPy coating can physically hinder the diffusion of LiPSs, as well as chemically adsorb LiPSs by the polar-polar mechanism. Benefiting from the synergistic effect of H-TiO x and PPy layer, the novel cathode delivered high specific capacities at different current rates (1130, 990, 932, 862, and 726 mAh g-1 at 0.1, 0.2, 0.3, 0.5, and 1C, respectively) and an ultralow capacity decay of 0.0406% per cycle after 1000 cycles at 1C. This work can not only indicate effectiveness of employing H-TiO x materials to realize the LiPSs immobilization but also shed light on the feasibility of combining different materials to achieve the multifunctional sulfur hosts for advanced Li-S batteries.

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial.

BACKGROUND: A subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. METHODS/DESIGN: A double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included. DISCUSSION: This is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. TRIAL REGISTRATION: The trial protocol has been registered on "ClinicalTrials.gov"with protocol ID "NAC-2015-TJAH" and ClinicalTrials.gov ID " NCT02972398 ".

Interleukin, tumor necrosis factor-α and C-reactive protein profiles in melancholic and non-melancholic depression: A systematic review.

OBJECTIVE: The current diagnostic criteria for major depressive disorder (MDD) do not allow prediction of prognosis and therapeutic response. A possible strategy to improve this situation is the identification of depression subtypes on the bases of biomarkers reflecting underlying pathological processes such as neuro-inflammation. METHODS: The PubMed/Medline database was searched until Apr 25th, 2017. In the initial search 1018 articles were retrieved, which were subsequently screened and only selected when the inclusion and exclusion criteria were fulfilled. RESULTS: Eight eligible studies were found. Overall, serum interleukin-6 and 1ß values were increased in the melancholic MDD subtype compared to controls and the non-melancholic MDD subtype. C-reactive protein was increased in non-melancholic MDD in 2 out of 4 studies, while there was no difference for tumor necrosis factor-α and interleukin-2 and 10. CONCLUSION: Given the paucity of eligible studies the tentative conclusion must be drawn that peripheral inflammation markers have limited added value thus far to distinguish between melancholic and non-melancholic depression. To allow for a more definitive conclusion, further research is warranted using a broader panel of inflammatory markers in MDD subtypes, preferably based on a general consensus regarding diagnostic criteria and subtype definitions.

A fuzzy neural network sliding mode controller for vibration suppression in robotically assisted minimally invasive surgery.

BACKGROUND: It is very important for robotically assisted minimally invasive surgery to achieve a high-precision and smooth motion control. However, the surgical instrument tip will exhibit vibration caused by nonlinear friction and unmodeled dynamics, especially when the surgical robot system is attempting low-speed, fine motion. METHODS: A fuzzy neural network sliding mode controller (FNNSMC) is proposed to suppress vibration of the surgical robotic system. Nonlinear friction and modeling uncertainties are compensated by a Stribeck model, a radial basis function (RBF) neural network and a fuzzy system, respectively. RESULTS: Simulations and experiments were performed on a 3 degree-of-freedom (DOF) minimally invasive surgical robot. The results demonstrate that the FNNSMC is effective and can suppress vibrations at the surgical instrument tip. CONCLUSIONS: The proposed FNNSMC can provide a robust performance and suppress the vibrations at the surgical instrument tip, which can enhance the quality and security of surgical procedures.

A zero phase adaptive fuzzy Kalman filter for physiological tremor suppression in robotically assisted minimally invasive surgery.

BACKGROUND: Hand physiological tremor of surgeons can cause vibration at the surgical instrument tip, which may make it difficult for the surgeon to perform fine manipulations of tissue, needles, and sutures. METHODS: A zero phase adaptive fuzzy Kalman filter (ZPAFKF) is proposed to suppress hand tremor and vibration of a robotic surgical system. The involuntary motion can be reduced by adding a compensating signal that has the same magnitude and frequency but opposite phase with the tremor signal. RESULTS: Simulations and experiments using different filters were performed. Results show that the proposed filter can avoid the loss of useful motion information and time delay, and better suppress minor and varying tremor. CONCLUSIONS: The ZPAFKF can provide less error, preferred accuracy, better tremor estimation, and more desirable compensation performance, to suppress hand tremor and decrease vibration at the surgical instrument tip. Copyright © 2016 John Wiley & Sons, Ltd.

Development of a multilayered polymeric DNA biosensor using radio frequency technology with gold and magnetic nanoparticles.

This study utilized the radio frequency (RF) technology to develop a multilayered polymeric DNA sensor with the help of gold and magnetic nanoparticles. The flexible polymeric materials, poly (p-xylylene) (Parylene) and polyethylene naphtholate (PEN), were used as substrates to replace the conventional rigid substrates such as glass and silicon wafers. The multilayered polymeric RF biosensor, including the two polymer layers and two copper transmission structure layers, was developed to reduce the total sensor size and further enhance the sensitivity of the biochip in the RF DNA detection. Thioglycolic acid (TGA) was used on the surface of the proposed biochip to form a thiolate-modified sensing surface for DNA hybridization. Gold nanoparticles (AuNPs) and magnetic nanoparticles (MNPs) were used to immobilize on the surface of the biosensor to enhance overall detection sensitivity. In addition to gold nanoparticles, the magnetic nanoparticles has been demonstrated the applicability for RF DNA detection. The performance of the proposed biosensor was evaluated by the shift of the center frequency of the RF biosensor because the electromagnetic characteristic of the biosensors can be altered by the immobilized multilayer nanoparticles on the biosensor. The experimental results show that the detection limit of the DNA concentration can reach as low as 10 pM, and the largest shift of the center frequency with triple-layer AuNPs and MNPs can approach 0.9 and 0.7 GHz, respectively. Such the achievement implies that the developed biosensor can offer an alternative inexpensive, disposable, and highly sensitive option for application in biomedicine diagnostic systems because the price and size of each biochip can be effectively reduced by using fully polymeric materials and multilayer-detecting structures.

Inhibition of nuclear factor-κB impairs reconsolidation of morphine reward memory in rats.

Drug addiction is a process associated with synaptic plasticity in which a drug of abuse affects the midbrain limbic system. Previous studies have indicated that drug abuse can be inhibited by disrupting the reconsolidation of a drug-related memory. Nuclear factor-κB (NF-κB) plays an important role in modulating different stages of memory, including reconsolidation, but its role in the reconsolidation of a reward memory has not been investigated. The aim of the present study was to examine the role of NF-κB in drug-related memory reconsolidation. We found that rats acquired morphine-induced conditioned place preference, which was inhibited by the NF-κB inhibitor SN50 administered after reexposure to a previously morphine-paired chamber (i.e., a memory retrieval process). The disruptive effect of SN50 on reward memory reconsolidation was reversed by systemic injections of the histone deacetylase inhibitor sodium butyrate. These results indicate that SN50 disrupts morphine-related memory reconsolidation by inhibiting NF-κB, and this effect can be reversed by inhibiting histone acetylation.