A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis.

Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.

Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity.

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.

Combined effects of sleep timing and nighttime sleep duration on non-alcoholic fatty liver disease.

BACKGROUND: While short sleep duration is linked to higher risk of non-alcoholic fatty liver disease (NAFLD), the combined effects of sleep timing and sleep duration on NAFLD are less explored. METHODS: In this cross-sectional study of 39,471 participants from Beijing-Tianjin-Hebei region of China, self-reported sleep information and ultrasonography-diagnosed NAFLD were obtained from Jan 2018 to Jan 2020. Sleep timing was categorized based on sleep midpoint: early-type (before 2:00 AM), intermediate-type (2:00-2:30 AM), and late-type (after 2:30 AM). We used multivariable logistic regression to explore the relationship between sleep timing, duration, and NAFLD. We analyzed sleep midpoint and duration categorically and continuously, and conducted stratification analyses by age, sex, body mass index, hypertension, diabetes, and dyslipidemia. RESULTS: Intermediate-type (OR: 1.15, 95% confidence interval: 1.05-1.26) and late-type sleep timing (OR: 1.08, 1.00-1.16) were associated with higher NAFLD risk compared to early-type. Additionally, longer sleep duration was linked to lower risk (OR: 0.92, 0.90-0.95 per hour increase). Notably, intermediate to late-type sleepers with normal sleep duration (7 to <8 h) exhibited a 20% higher NAFLD risk compared to early-type sleepers with the same duration (OR: 1.20, 1.04-1.39). The increased NAFLD risk associated with intermediate to late sleep timing was particularly evident in men, hypertension, and prediabetes or diabetes participants. CONCLUSIONS: Intermediate to late sleep timing, even with normal sleep duration, is associated with increased NAFLD risk. These findings underscore the importance of considering both sleep timing and sleep duration for NAFLD prevention, especially in men and individuals with cardiometabolic conditions.

Betaine regulates adipogenic and osteogenic differentiation of hAD-MSCs.

BACKGROUND: With an ageing population, the incidence of bone loss and obesity are increasing. Numerous studies emphasized the multidirectional differentiation ability of mesenchymal stem cells (MSCs), and reported betaine modulated the osteogenic differentiation and adipogenic differentiation of MSCs in vitro. We wondered how betaine affected the differentiation of hAD-MSCs and hUC-MSCs. METHODS AND RESULTS: ALP staining and alizarin red S (ARS) staining were proved 10 mM betaine significantly increased the number of ALP-positive cells and plaque calcified extracellular matrices, accompanying by the up-regulation of OPN, Runx-2 and OCN. Oil red O staining demonstrated the number and size of lipid droplets were reduced, the expression of adipogenic master genes such as PPARγ, CEBPα and FASN were down-regulated simultaneously. For further investigating the mechanism of betaine on hAD-MSCs, RNA-seq was performed in none-differentiation medium. The Gene Ontology (GO) analysis showed fat cell differentiation and bone mineralization function terms were enriched, and KEGG showed PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction pathways were enriched in betaine treated hAD-MSCs, demonstrated betaine had a positive inducing effect on osteogenic of hAD-MSCs in the non-differentiation medium in vitro, which is opposite to the effect on adipogenic differentiation. CONCLUSIONS: Our study demonstrated that betaine promoted osteogenic and compromised adipogenic differentiation of hUC-MSCs and hAD-MSCs upon low concentration administration. PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction were significantly enriched under betaine-treated. We showed hAD-MSCs were more sensitive to betaine stimulation and have a better differentiation ability than hUC-MSCs. Our results contributed to the exploration of betaine as an aiding agent for MSCs therapy.

Long-term exposure to ambient ozone at workplace is positively and non-linearly associated with incident hypertension and blood pressure: longitudinal evidence from the Beijing-Tianjin-Hebei medical examination cohort.

BACKGROUND: There is limited longitudinal evidence on the hypertensive effects of long-term exposure to ambient O3. We investigated the association between long-term O3 exposure at workplace and incident hypertension, diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in general working adults. METHODS: We conducted a cohort study by recruiting over 30,000 medical examination attendees through multistage stratified cluster sampling. Participants completed a standard questionnaire and comprehensive medical examination. Three-year ambient O3 concentrations at each employed participant's workplace were estimated using a two-stage machine learning model. Mixed-effects Cox proportional hazards models and linear mixed-effects models were used to examine the effect of O3 concentrations on incident hypertension and blood pressure parameters, respectively. Generalized additive mixed models were used to explore non-linear concentration-response relationships. RESULTS: A total of 16,630 hypertension-free working participants at baseline finished the follow-up. The mean (SD) O3 exposure was 45.26 (2.70) ppb. The cumulative incidence of hypertension was 7.11 (95% CI: 6.76, 7.47) per 100 person-years. Long-term O3 exposure was independently, positively and non-linearly associated with incident hypertension (Hazard ratios (95% CI) for Q2, Q3, and Q4 were 1.77 (1.34, 2.36), 2.06 (1.42, 3.00) and 3.43 (2.46, 4.79), respectively, as compared with the first quartile (Q1)), DBP (ß (95% CI) was 0.65 (0.01, 1.30) for Q2, as compared to Q1), SBP (ß (95% CI) was 2.88 (2.00, 3.77), 2.49 (1.36, 3.61) and 2.61 (1.64, 3.58) for Q2, Q3, and Q4, respectively), PP (ß (95% CI) was 2.12 (1.36, 2.87), 2.03 (1.18, 2.87) and 2.14 (1.38, 2.90) for Q2, Q3, and Q4, respectively), and MAP (ß (95% CI) was 1.39 (0.76, 2.02), 1.04 (0.24, 1.84) and 1.12 (0.43, 1.82) for Q2, Q3, and Q4, respectively). The associations were robust across sex, age, BMI, and when considering PM2.5 and NO2. CONCLUSIONS: To our knowledge, this is the first cohort study in the general population that demonstrates the non-linear hypertensive effects of long-term O3 exposure. The findings are particularly relevant for policymakers and researchers involved in ambient pollution and public health, supporting the integration of reduction of ambient O3 into public health interventions.

Revitalizing Iron Redox by Anion-Insertion-Assisted Ferro- and Ferri-Hydroxides Conversion at Low Alkalinity.

Iron hydroxides are desirable alkaline battery electrodes for low cost and environmental beneficence. However, hydrogen evolution on charging and Fe3O4 formation on discharging cause low storage capacity and poor cycling life. We report that green rust (GR) (Fe2+4Fe3+2 (HO-)12SO4), formed via sulfate insertion, promotes Fe(OH)2/FeOOH conversion and shows a discharge capacity of ∼211 mAh g-1 in half-cells and Coulombic efficiency of 93% after 300 cycles in full-cells. Theoretical calculations show that Fe(OH)2/FeOOH conversion is facilitated by intercalated sulfate anions. Classical molecular dynamics simulations reveal that electrolyte alkalinity strongly impacts the energetics of sulfate solvation, and low alkalinity ensures fast transport of sulfate ions. Anion-insertion-assisted Fe(OH)2/FeOOH conversion, also achieved with Cl- ion, paves a pathway toward efficient utilization of Fe-based electrodes for sustainable applications.

The effect of gradient nonlinearities on fiber orientation estimates from spherical deconvolution of diffusion magnetic resonance imaging data.

Gradient nonlinearities in magnetic resonance imaging (MRI) cause spatially varying mismatches between the imposed and the effective gradients and can cause significant biases in rotationally invariant diffusion MRI measures derived from, for example, diffusion tensor imaging. The estimation of the orientational organization of fibrous tissue, which is nowadays frequently performed with spherical deconvolution techniques ideally using higher diffusion weightings, can likewise be biased by gradient nonlinearities. We explore the sensitivity of two established spherical deconvolution approaches to gradient nonlinearities, namely constrained spherical deconvolution (CSD) and damped Richardson-Lucy (dRL). Additionally, we propose an extension of dRL to take into account gradient imperfections, without the need of data interpolation. Simulations show that using the effective b-matrix can improve dRL fiber orientation estimation and reduces angular deviations, while CSD can be more robust to gradient nonlinearity depending on the implementation. Angular errors depend on a complex interplay of many factors, including the direction and magnitude of gradient deviations, underlying microstructure, SNR, anisotropy of the effective response function, and diffusion weighting. Notably, angular deviations can also be observed at lower b-values in contrast to the perhaps common assumption that only high b-value data are affected. In in vivo Human Connectome Project data and acquisitions from an ultrastrong gradient (300 mT/m) scanner, angular differences are observed between applying and not applying the effective gradients in dRL estimation. As even small angular differences can lead to error propagation during tractography and as such impact connectivity analyses, incorporating gradient deviations into the estimation of fiber orientations should make such analyses more reliable.

Spherical deconvolution with tissue-specific response functions and multi-shell diffusion MRI to estimate multiple fiber orientation distributions (mFODs).

In diffusion MRI, spherical deconvolution approaches can estimate local white matter (WM) fiber orientation distributions (FOD) which can be used to produce fiber tractography reconstructions. The applicability of spherical deconvolution to gray matter (GM), however, is still limited, despite its critical role as start/endpoint of WM fiber pathways. The advent of multi-shell diffusion MRI data offers additional contrast to model the GM signal but, to date, only isotropic models have been applied to GM. Evidence from both histology and high-resolution diffusion MRI studies suggests a marked anisotropic character of the diffusion process in GM, which could be exploited to improve the description of the cortical organization. In this study, we investigated whether performing spherical deconvolution with tissue specific models of both WM and GM can improve the characterization of the latter while retaining state-of-the-art performances in WM. To this end, we developed a framework able to simultaneously accommodate multiple anisotropic response functions to estimate multiple, tissue-specific, fiber orientation distributions (mFODs). As proof of principle, we used the diffusion kurtosis imaging model to represent the WM signal, and the neurite orientation dispersion and density imaging (NODDI) model to represent the GM signal. The feasibility of the proposed approach is shown with numerical simulations and with data from the Human Connectome Project (HCP). The performance of our method is compared to the current state of the art, multi-shell constrained spherical deconvolution (MSCSD). The simulations show that with our new method we can accurately estimate a mixture of two FODs at SNR≥50. With HCP data, the proposed method was able to reconstruct both tangentially and radially oriented FODs in GM, and performed comparably well to MSCSD in computing FODs in WM. When performing fiber tractography, the trajectories reconstructed with mFODs reached the cortex with more spatial continuity and for a longer distance as compared to MSCSD and allowed to reconstruct short trajectories tangential to the cortical folding. In conclusion, we demonstrated that our proposed method allows to perform spherical deconvolution of multiple anisotropic response functions, specifically improving the performances of spherical deconvolution in GM tissue.

Generalized Richardson-Lucy (GRL) for analyzing multi-shell diffusion MRI data.

Spherical deconvolution is a widely used approach to quantify the fiber orientation distribution (FOD) from diffusion MRI data of the brain. The damped Richardson-Lucy (dRL) is an algorithm developed to perform robust spherical deconvolution on single-shell diffusion MRI data while suppressing spurious FOD peaks due to noise or partial volume effects. Due to recent progress in acquisition hardware and scanning protocols, it is becoming increasingly common to acquire multi-shell diffusion MRI data, which allows for the modelling of multiple tissue types beyond white matter. While the dRL algorithm could, in theory, be directly applied to multi-shell data, it is not optimised to exploit its information content to model the signal from multiple tissue types. In this work, we introduce a new framework based on dRL - dubbed generalized Richardson-Lucy (GRL) - that uses multi-shell data in combination with user-chosen tissue models to disentangle partial volume effects and increase the accuracy in FOD estimation. Further, GRL estimates signal fraction maps associated to each user-selected model, which can be used during fiber tractography to dissect and terminate the tracking without need for additional structural data. The optimal weighting of multi-shell data in the fit and the robustness to noise and to partial volume effects of GRL was studied with synthetic data. Subsequently, we investigated the performance of GRL in comparison to dRL and to multi-shell constrained spherical deconvolution (MSCSD) on a high-resolution diffusion MRI dataset from the Human Connectome Project and on an MRI dataset acquired at 3T on a clinical scanner. In line with previous studies, we described the signal of the cerebrospinal-fluid and of the grey matter with isotropic diffusion models, whereas four diffusion models were considered to describe the white matter. With a third dataset including small diffusion weightings, we studied the feasibility of including intra-voxel incoherent motion effects due to blood pseudo-diffusion in the modelling. Further, the reliability of GRL was demonstrated with a test-retest scan of a subject acquired at 3T. Results of simulations show that GRL can robustly disentangle different tissue types at SNR above 20 with respect to the non-weighted image, and that it improves the angular accuracy of the FOD estimation as compared to dRL. On real data, GRL provides signal fraction maps that are physiologically plausible and consistent with those obtained with MSCSD, with correlation coefficients between the two methods up to 0.96. When considering IVIM effects, a high blood pseudo-diffusion fraction is observed in the medial temporal lobe and in the sagittal sinus. In comparison to dRL and MSCSD, GRL provided sharper FODs and less spurious peaks in presence of partial volume effects, but the FOD reconstructions are also highly dependent on the chosen modelling of white matter. When performing fiber tractography, GRL allows to terminate fiber tractography using the signal fraction maps, which results in a better tract termination at the grey-white matter interface or at the outer cortical surface. In terms of inter-scan reliability, GRL performed similarly to or better than compared methods. In conclusion, GRL offers a new modular and flexible framework to perform spherical deconvolution of multi-shell data.

Hydroxysteroid sulfotransferase 2B1 affects gastric epithelial function and carcinogenesis induced by a carcinogenic agent.

BACKGROUND: A healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. Oxysterols provided from food or cholesterol oxidation in the gastric epithelium may be further sulfated by hydroxysteroid sulfotransferase 2B1 (SULT2B1), which is highly abundant in the gastric epithelium. However, the effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear. METHODS: A mouse gastric tumor model was established using carcinogenic agent 3-methylcholanthrene (3-MCA). A SULT2B1 deletion (SULT2B1-/-) human gastric epithelial line GES-1 was constructed by CRISPR/CAS9 genome editing system. RESULTS: The gastric tumor incidence was higher in the SULT2B1-/- mice than in the wild-type (WT) mice. In gastric epithelial cells, adenovirus-mediated SULT2B1b overexpression reduced the levels of oxysterols, such as 24(R/S),25-epoxycholesterol (24(R/S),25-EC) and 27-hydroxycholesterol (27HC). This condition also increased PI3K/AKT signaling to promote gastric epithelial cell proliferation, epithelization, and epithelial development. However, SULT2B1 deletion or SULT2B1 knockdown suppressed PI3K/AKT signaling, epithelial cell epithelization, and wound healing and induced gastric epithelial cell malignant transition upon 3-MCA induction. CONCLUSIONS: The abundant SULT2B1 expression in normal gastric epithelium might maintain epithelial function via the PI3K/AKT signaling pathway and suppress gastric carcinogenesis induced by a carcinogenic agent.