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The aim of this study was to investigate the metabolic changes associated with the anti-obesity effects of fermented blackberry extracts in the liver tissues of high-fat-diet-fed mice using mass spectrometry-based metabolomics analysis. C57BL/6J mice were divided into eight groups: normal-diet-fed mice, high-fat-diet-fed mice, high-fat diet treated with blackberry extract, high-fat-diet mice treated with blackberry fermented by L. plantarum, and high-fat diet with blackberry fermented by L. brevis. After 12 weeks, the high-fat-diet group exhibited a greater increase in liver weight compared to the control group, and among the groups, the group administered with blackberry fermented with L. plantarum showed the most pronounced reduction in liver weight. As the primary organ responsible for amino acid metabolism, the liver is crucial for maintaining amino acid homeostasis. In our study, we observed that the levels of several essential amino acids, including isoleucine and valine, were decreased by the high-fat diet, and were recovered by administration of blackberry extract fermented with L. plantarum. Our results demonstrated the potential of blackberry extract fermented with L. plantarum as a functional material for metabolic disorders by restoring some of the amino acid metabolism disturbances induced by a high-fat diet.

Background: The prevalence of atherosclerotic cardiovascular disease appears to be reduced, according to a large body of research, by lowering blood levels of the ratio of low-density lipoprotein cholesterol (LDL-C)/ high-density lipoprotein cholesterol (HDL-C), triglyceride (TG)/HDL-C, and LDL-C. Objective: The objective of the investigation was to determine the safety and endurance of policosanol (20 mg/d), as well as its efficacy in healthy individuals. Two parallel groups in this randomized, double-blind, placebo-controlled human experiment received either a policosanol (20 mg/d) or a placebo for eight weeks. 80 people were randomly assigned, with a mean (SD) age (years) of 42.61 (13.51), a mean (SD) BMI (kg/m2) of 24.53 (3.57), a mean (SD) weight (kg) of 66.71 (14.30), and a mean (SD) height (cm) of 164.21. (7.99). Results: At 8 weeks, when compared to the baseline group, the policosanol (20 mg/d) batch displayed considerably greater LDL-C (-4.87 ± 11.30 mg/dL; p = 0.014), total cholesterol (-6.82 ± 14.32 mg/dL; p = 0.007), triglyceride (-9.37 ± 19.27 mg/dL; p = 0.008), non HDL-C reductions (-10.32 ± 13.75 mg/dL; p = 0.0001), and significantly greater augmentation of HDL-C (3.50 ± 4.55 mg/dL; p = 0.010). Policosanol (20 mg/d) treatment also significantly reducing the serum levels of TC/HDL-C (p = 0.0001) and LDL-C/HDL-C (p = 0.0002), triglyceride/HDL-C (p = 0.001), and T-cholesterol-HDL-C/HDL-C (p = 0.0001) ratios. Conclusion: In humans, policosanol delivery resulted in a lowering of LDL-C levels and an improvement in other lipid markers, demonstrating the product potential to regulate hypercholesterolemia.

Although the seasonal prediction skill of climate models has improved significantly in recent decades, the prediction skill of the Arctic Oscillation (AO), the dominant climate mode over the Northern Hemisphere, remains poor. Additionally, the local representation of AO impacts has diverged from observations, which limits seasonal prediction skill of climate models. In this study, we attempted to improve prediction skill of surface air temperature (SAT) with two post-processing on dynamical model’s seasonal forecast: (1) correction of the AO impact on SAT pattern, and (2) correction of AO index (AOI). The first correction involved replacing the inaccurately simulated impact of AO on SAT with that observed. For the second correction, we employed a empirical prediction model of AOI based on multiple linear regression model based on three precursors: summer sea surface temperature, autumn sea-ice concentration, and autumn snow cover extent. The application of the first correction led to a decrease in prediction skills. However, a significant improvement in SAT prediction skills is achieved when both corrections are applied. The average correlation coefficients for the North America and Eurasian regions increased from 0.23 and 0.06 to 0.28 and 0.30, respectively.

Objective: This study aimed to assess how well Amomum villosum water extract (AVE) assisted overweight to moderately obese people in losing weight. Methods: Eighty participants were chosen at random for the AVE group or the placebo group for this experiment. Subjects were given two tablets of the test substance after their two consistent meals daily for 12 weeks. At the starting and completion of the experiment, measurements of body mass index (BMI), body weight, percent body fat, body fat mass, visceral adipose tissue (VAT), lean body mass, subcutaneous adipose tissue (SAT), percent VAT (%), and percent SAT (%) were taken. Before and after the study, blood samples were obtained for safety laboratory parameters. Results: After taking the products for 12 weeks, the AVE group lost considerably more weight than the placebo group (-2.04 ± 3.04 kg vs −0.30 ± 2.88 kg, respectively; P

Ethnopharmacological relevance: Ginger (Zingiber officinale Roscoe) has been used for food and applied in Ayurvedic medicine in India for thousands of years. With a reputation for strong anti-inflammatory properties, it has been used for to treat colds, migraines, nausea, arthritis, and high blood pressure in China and Southeast Asia. The physiological activity of ginger is attributed to its functional components, including gingerol and shogaol, and their derivatives. Aim of the study: We aimed to investigate the effects of 8- and 10-shogaol and their bioactive signaling mechanisms in a dextran sodium sulfate (DSS)-induced colitis mouse model. The anti-colitis efficacy of 6-, 8-, and 10-derivatives of gingerol and shogaol was comparatively analyzed. Materials and methods: Colitis was induced by providing mice with drinking water containing 5% DSS (w/v) for 8 days. The 6-, 8-, and 10-derivatives of gingerol and shogaol were orally administered for two weeks at a dose of 30 mg/kg. Changes in body weight and disease activity index were measured. The levels of pro-inflammatory cytokines, iNOS and COX-2, as well as the phosphorylation of NF-κB were analyzed using ELISA, PCR, or western blotting. Mucin expression and mRNA levels were measured using alcian blue staining and PCR, respectively. The tight-junction-associated proteins occludin and ZO-1 were assessed using immunohistological staining. Results: The 6-, 8-, and 10-derivatives of gingerol and shogaol exhibited anti-inflammatory effects by regulating NF-κB signaling. Among the compounds administered, 10-shogaol was the most effective against DSS-induced inflammation. Comparative analysis of the chemical structure showed that shogaol, a dehydrated analog of gingerol, was more effective. 6- and 10-shogaol showed similar effects on DSS-induced morphological changes in the colonic mucus layer, mucin expression, and tight junction proteins. Conclusions: 6-, 8-, and 10-Gingerol and 6-, 8-, and 10-shogaol significantly improved the clinical symptoms and intestinal epithelial barrier damage in DSS-induced colitis in mice. The derivatives effectively inhibited DSS-induced inflammation through the regulation of NF-κB signaling. Moreover, 10-shogaol showed the most potent anti-inflammatory effect among the six compounds used in this study. The results indicate that 8- and 10-shogaol, both main ingredients in ginger, may serve as therapeutic candidates for the treatment of colitis.

Amomum villosum Lour. (Zingiberaceae) is an herbal medicine used in Asian countries for various ailments. In the current experiment, the effect of AV water extract (AVE) on cholesterol-lowering capabilities along with its essential bio-molecular mechanisms have been examined. The efficiency of AVE against high-cholesterol diet (HCD)-generated hyperlipidemia was investigated using C57BL/6 mice. Mice have been divided to six categories: control group (normal diet), high-cholesterol diet (HCD), and HCD treated with AVE at 100, 200, and 500 mg/kg, or simvastatin 40 mg/kg for four weeks. AVE treated animal groups (100, 200, 500 mg/kg) had markedly lessened body mass increase (p

A large number of Bacillus strains have been isolated from various environments and many of them have great potential as cell factories. However, they have been rarely developed as cell factories due to their poor transformation efficiency. In this study, we developed a highly efficient plasmid delivery system for undomesticated Bacillus strains using a modified integrative and conjugative element (MICE), which was designed to be activated by an inducer, prevent self-transfer, and deliver desired plasmids to the recipient cells. The MICE system was demonstrated to successfully introduce a gfp-containing plasmid into all 41 undomesticated Bacillus subtilis strains tested and eight other Bacillus species. The MICE was used to deliver a cytosine base editor (CBE)-based multiplex genome-editing tool for the cell factory engineering of the Bacillus species. The introduced CBE enabled one-step inactivation of the major extracellular protease genes of the tested strains. The engineered strains were used as hosts for heterologous expression of nattokinase, which resulted in various enzyme expression levels. The results suggested that the MICE and CBE systems can be powerful tools for genetic engineering of undomesticated Bacillus strains, and greatly contribute to the expansion of the Bacillus cell factory.

GloSea5, a seasonal forecast system of the UK Met Office, shows reasonable skill among state-of-the-art operational seasonal forecast systems. However, the average surface temperature (T2m) in winter (December–February) of GloSea5 is particularly low in East Asia. To improve the seasonal forecast skill over East Asia, we focused on the high skill score of global teleconnection patterns simulated by GloSea5. Among the well-predicted teleconnection patterns, we selected those highly correlated with the East Asian T2m: East Atlantic (EA), Polar/Eurasia (PE), East Atlantic/Western Russia (EAWR), and West Pacific (WP) patterns. A multiple linear regression model was constructed using the selected teleconnection indices as predictors. These results are promising. The statistical skill-score evaluation of the constructed linear regression model using the anomaly correlation coefficient (ACC), root mean squared error (RMSE), and mean-squared skill score (MSSS) showed an improvement in the predicted T2m of East Asia, where the values of ACC and MSSS increased by 0.25 and 0.37, respectively, and the RMSE decreased by 0.63 compared to the dynamic forecast model results. These results suggest that a well-designed combined statistical and dynamical approach for seasonal prediction can be beneficial for some regions where the predictability of the dynamic model exhibits a low value.

This study investigates the sensitivity of the boreal winter prediction skill of Community Atmosphere Model 5 to the choice of the dynamical core. Both finite volume (FV) and spectral element (SE) dynamical cores are tested. An additional FV with the SE topography (FV _SE ) is also conducted to isolate the possible influence of the topography. The three dynamical core experiments, which ran from 2001/2002–2017/2018, are validated using Japanese 55 year reanalysis data. It turns out that the SE (−4.27 °C) has a smaller cold bias in boreal-winter surface air temperature (SAT) than the FV (−5.17 °C) and FV _SE (−5.29 °C), particularly in North America, East Asia, and Southern Europe/Northern Africa. Significant North Atlantic Oscillation-like biases are also identified in the mid-troposphere. These biases affect seasonal prediction skills. Although the overall prediction skills of boreal-winter SAT, quantified by the anomaly correlation coefficient (ACC), and root-mean-square error (RMSE), are reasonably good (ACC = 0.40 and RMSE = 0.47 in the mean values of SE, FV, and FV _SE ), they significantly differ from one region to another, depending on the choice of dynamical cores. For North America and Southern Europe/Northern Africa, SE shows better skills than FV _SE and FV. Conversely, in East Asia, FV and FV _SE outperform SE. These results suggest that the appropriate choice of the dynamical cores and the bottom boundary conditions could improve the boreal-winter seasonal prediction on a regional scale.

Amomum villosum Lour. is commonly used in Asian countries as an herbal remedy to medicate several diseases including type 2 diabetes. In this animal experiment, we examined the influence of Amomum villosum water extract (AVE) against metabolic variations in high-fat diet (HFD)-induced obesity in C57BL/6 mice. Mice were nourishing with a normal diet (control), high-fat diet (HFD), HFD + AVE 100 mg/kg body weight (b.wt.)/day, HFD + AVE 200 mg/kg b.wt./day, and HFD + AVE 500 mg/kg b.wt./day for 7 weeks. The AVE (100, 200, and 500 mg/kg)-treated animals exhibited substantial decreases in body mass, fat mass, adipocyte hypertrophy, and epididymal white adipose tissue (eWAT) collate to the HFD-fed group. AVE treatment also reduced hepatic triglyceride level and significantly increased the adiponectin expression in adipocytes. Furthermore, AVE treatment significantly inhibited adipogenesis in the AVE group by reducing the mRNA expression of sterol regulatory element-binding protein1 (SREBP1), fatty acid synthase (FAS), CCAAT/enhancer binding protein (C/EBP)-α, peroxisome proliferator-activated receptor (PPAR)-γ, and tumor necrosis factor (TNF)-α agreeing to the HFD-fed animals. These research outcomes recommend that AVE is possibly valuable for the prevention of HFD-induced obesity via modification of various pathways related with adipogenesis and food consumption.

Genome-based identification of new antibiotics is emerging as an alternative to traditional methods. However, uncovering hidden antibiotics under the background of known antibiotics remains a challenge. To over this problem using a quick and effective genetic approach, we developed a multiplex genome editing system using a cytosine base editor (CBE). The CBE system achieved simultaneous double, triple, quadruple, and quintuple gene editing with efficiencies of 100, 100, 83, and 75%, respectively, as well as the 100% editing efficiency of single targets in Bacillus subtilis. Whole-genome sequencing of the edited strains showed that they had an average of 8.5 off-target single-nucleotide variants at gRNA-independent positions. The CBE system was used to simultaneously knockout five known antibiotic biosynthetic gene clusters to leave only an uncharacterized polyketide biosynthetic gene cluster in Paenibacillus polymyxa E681. The polyketide showed antimicrobial activities against gram-positive bacteria, but not gram-negative bacteria and fungi. Therefore, our findings suggested that the CBE system might serve as a powerful tool for multiplex genome editing and greatly accelerating the unraveling of hidden antibiotics in Bacillus and Paenibacillus species.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, and the incidence of IBD is increasing every year owing to changes in dietary structure. Although the exact pathogenesis of IBD is still unclear, recent evidence suggests that gut dysbiosis is closely associated with IBD pathogenesis. Cheonggukjang is a traditional Korean fermented soybean paste produced using traditional and industrial methods, and contains probiotics, which affect the gut microbiota composition. However, the protective effect of Cheonggukjang against IBD is unknown. In this study, we investigated the bacterial community structure of traditional and commercial Cheonggukjang samples, as well as the protective effect of Cheonggukjang on a dextran sulfate sodium (DSS)-induced colitis mouse model. Traditional and commercial Cheonggukjang were found to contain various type of useful probiotics in their bacterial community structure. Cheonggukjang reduced the progression of DSS-induced symptoms, such as body weight loss, colonic shortening, disease activity index, and histological changes. Further, Cheonggukjang improved the intestinal epithelial barrier integrity on DSS-induced colitis mice. In addition, Cheonggukjang suppressed the expression of proinflammatory cytokines and inflammatory mediators through the inactivation of NF-κB and MAPK signaling pathways. These results indicate that Cheonggukjang exerts protective effects against DSS-induced colitis, suggesting its possible application as a functional food for improving inflammatory diseases.

Echinacea purpurea (EP) has been widely used to treat upper respiratory infections, influenza, and the common cold. It can also exert various pharmacological activities, such as anti-inflammatory and anti-allergic effects. However, the potential of EP to modulate immune reactions remains unclear. Therefore, we evaluated the immunostimulatory effects of EP in cyclophosphamide (CP)-induced immunosuppressed mice. In this study, EP extract (12.5, 25, or 50 mg/kg) was orally administered to cyclophosphamide-induced immunosuppressed BALB/c mice. Then, indexes of immune organs, including the spleen and thymus, were recorded. Splenocyte proliferation and natural killer (NK) cell activities were measured by lactate dehydrogenase assay. Subsets of T cells, such as CD4+ and CD8+, were measured by flow cytometry, and immuno-cytokines, such as interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, were measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The immunosuppressed mice showed decreased thymus and spleen indexes and immune cell activities. Treatment of EP elevated the indexes of immune organs, splenocyte proliferation, and NK cell activities in CP-induced immunosuppressed mice. Simultaneously, administration of EP reversed the CP-induced decrease in T-lymphocyte subsets (CD4+ and CD8+) and immunocytokines (IL-2, TNF-α, and IFN-γ). Taken together, these findings suggest that EP could be used to enhance health and immunity in immunosuppressed conditions.

Ultraviolet (UV)-irradiation causes an overproduction of matrix metalloproteinases (MMPs) and collagen (COL) degradation causing skin sunburn, inflammation, or photoaging in human. In this study, we prepared callus from Tiarella polyphylla D. Don (T. polyphylla) stem and its phytochemical profiles were analyzed using HPLC-MWD. The effects of T. polyphylla callus extract evaluated against on UVB-induced damage in human foreskin fibroblast (Hs68). Hs68 was exposed to UVB in the presence or absence of T. polyphylla callus extract at concentrations of 100 and 250 µg/mL. Cell damage caused by UVB was inhibited by T. polyphylla callus extract, which was tested by cell viability and caspase 3 activity in Hs68 cells. Further experiment revealed that T. polyphylla extract suppressed the level of MMP-1, but increased the level of type I procollagen. In addition, T. polyhylla callus extract inhibited UVB-mediated COL (-1 and -3) protein degradation and MMP (-1, 2, and -3) overexpression in Hs68. These results suggest that T. polyphylla callus extract has considerable potential as a cosmetic ingredient with anti-aging effects. [ABSTRACT FROM AUTHOR]

This study investigates the prediction skill of sub-seasonal prediction models that vary based on the choice of two dynamical cores: the finite volume (FV) dynamical core on a latitude-longitude grid system and the spectral element (SE) dynamical core on a cubed-sphere grid system. Recent research showed that the SE dynamical core on a uniform grid system increases parallel scalability and removes the need for polar filters for mitigating uncertainty in climate prediction, particularly for the Arctic region. However, it still remains questionable whether the choice of dynamical cores can actually yield significant changes in prediction skill. To tackle this issue, we implemented a sub-seasonal prediction model based on the Community Atmospheric Model version 5 by incorporating the above two dynamical cores with virtually the same physics schemes. Sub-seasonal prediction skills of the SE dynamical core and FV dynamical core are verified with ERA-Interim reanalysis during the early winter (November-December) and the late winter (January-February) from 2001/2002 to 2017/2018. The prediction skills of two different dynamical cores were significantly different regardless of the similar physics scheme. In the ocean, the predictability of the SE dynamical core is similar to that of the FV dynamical core, mostly because our simulation configuration imposes the same boundary and initial conditions at the surface. Notable differences in the one-month predictability between the two cores are observed for the wintertime Arctic and mid-latitudes, particularly over North America and Eurasia continents. With a one-month lead, the SE dynamical core exhibited higher predictability over North America in late winter (r ~ 0.45 in SE, r ~ 0.10 in FV) whereas the FV dynamical core showed relatively higher predictability in East Asia and Eurasia in early winter (r ~ 0.15 in SE, r ~ 0.43 in FV). Therefore, we conclude that caution is needed when selecting the dynamical cores of sub-seasonal prediction models. Partially, these differences can be ascribed to the different manifestations of Arctic-mid-latitude linkage in the two dynamical cores; the SE dynamical core captures warmer Arctic and colder mid-latitudes relatively better than the FV dynamical core. [ABSTRACT FROM AUTHOR]

Background: Hominis Placenta (HP) known as a restorative medicine in Traditional Chinese Medicine (TCM), has been widely applied in the clinics of Korea and China as an anti-aging agent to enhance the regeneration of tissue. This study was conducted to investigate whether topical treatment of HP promotes hair regrowth in the animal model. Methods: The dorsal hairs of 8-week-old C57BL/6 mice were depilated to synchronize hair follicles to the anagen phase. HP was applied topically once a day for 15 days. Hair growth was evaluated visually and microscopically. The incorporation of bromodeoxyuridine (BrdU) and expression of proliferating cell nuclear antigen (PCNA), fibroblast growth factor-7 (FGF-7) in dorsal skin tissue was examined by immunohistochemical analysis. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of FGF-7. Results: HP exhibited potent hair growth-promoting activity in C57BL/6 mice. Gross examination indicated that HP markedly increased hair regrowth as well as hair density and diameter. Histologic analysis showed that HP treatment enhanced the anagen induction of hair follicles. Immunohistochemical analysis revealed that BrdU incorporation and the expressions of PCNA were increased by treatment of HP. HP treatment significantly increased the expression of FGF-7, which plays pivotal roles to maintain anagen phase both protein and mRNA levels. Conclusions: Taken together, our results indicate that HP has a potent hair growth-promoting activity; therefore, it may be a good candidate for the treatment of alopecia. [ABSTRACT FROM AUTHOR]

Background Saussurea lappa (SL) has been used as a traditional herbal medicine to treat abdominal pain and tenesmus, and has been suggested to possess various biological activities, including antitumor, anti-ulcer, anti-inflammatory, anti-viral, and cardiotonic activities. The effect of SL on breast cancer metastasis, however, is unknown. Cell migration and invasion are crucial in neoplastic metastasis. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix, is a major component in cancer cell invasion. Methods Cell viability was examined by MTT assay, whereas cell motility was measured by invasion assay. Western blot, Real-time PCR, and Zymography assays were used to investigate the inhibitory effects of ESL on matrix metalloproteinase-9 (MMP-9) expression level in MCF- 7 cells. EMSA confirmed the inhibitory effects of ESL on DNA binding of NF- κB in MCF- 7 cells. Results Cells threated with various concentrations of Saussurea lappa (ESL) for 24 h. Concentrations of 2 or 4 μM did not lead to a significant change in cell viability or morphology. Therefore, subsequent experiments utilized the optimal non-toxic concentration (2 or 4 μM) of ESL. In this study, we investigated the inhibitory effect of ethanol extract of ESL on MMP-9 expression and cell invasion in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF- 7 cells. ESL inhibited the TPA-induced transcriptional activation of nuclear factor-kappa B (NF-κB). However, this result obtained that ESL did not block the TPA-induced phosphorylation of the kinases: p38, ERK, and JNK. Therefore, ELS-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of NF-kB pathway in MCF-7 cells. Conclusions These results indicate that ELS-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of NF-kB pathway in MCF-7 cells. Thus, ESL has potential for controlling breast cancer invasiveness in vitro. [ABSTRACT FROM AUTHOR]

Introduction. Crotonis fructus (CF) is the mature fruit of Croton tiglium L. and has been used for the treatment of gastrointestinal disturbance in Asia. It is well known that the main component of CF is croton oil (CO). The present study is to investigate the effects of CF extracts (CFE) and CO on lipolysis in OP9 adipocytes. Methods. Glycerol release to the culture supernatants was used as a marker of adipocyte lipolysis. Results. Treatment with various concentrations of CFE and CO stimulates glycerol release in a dose-dependent manner. The increase in glycerol release by CFE is more potent than isoproterenol, which is a β-adrenergic agonist as a positive control in our system. The increased lipolysis by CFE and CO was accompanied by an increase of phosphorylated hormone sensitive lipase (pHSL) but not nonphosphorylated HSL protein and mRNA. Pretreatment with H89, which is a protein kinase A inhibitor, significantly abolished the CFE- and CO-induced glycerol release in OP9 adipocytes. These results suggest that CFE and CO may be a candidate for the development of a lipolysis-stimulating agent in adipocytes. [ABSTRACT FROM AUTHOR]

The rhizome of Alisma orientale (Alismatis rhizome) has been used in Asia for promoting diuresis to eliminate dampness from the lower-jiao and to expel heat. In this study, an ethanol extract of the rhizome of Alisma orientale (AOE)was prepared and its effects on adipocyte differentiation of OP9 cells were investigated. Treatment with AOE in a differentiation medium for 5 days resulted in dose-dependent inhibition of lipid droplet formation in OP9 cells. Furthermore, AOE significantly inhibited adipocyte differentiation by downregulating the expression of the master transcription factor of adipogenesis, peroxisome proliferation-activity receptor γ (PPARγ), and related genes, including CCAAT/enhancer binding protein β (C/EBPβ), fatty acid-binding protein (aP2), and fatty acid synthase (FAS). AOE exerted its inhibitory effects primarily during the early adipogenesis stage (days 1-2), at which time it also exerted dose-dependent inhibition of the expression of C/EBPβ, a protein related to the inhibition of mitotic clonal expansion. Additionally, AOE decreased the expression of autophagy-related proteins, including beclin 1, and the autophagy-related genes, (Atg) 7 and Atg12. Our results indicate that AOE's inhibitory effects on adipocyte differentiation of OP9 cells are mediated by reduced C/EBPβ expression, causing inhibition of mitotic clonal expansion and autophagy. [ABSTRACT FROM AUTHOR]