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Background: The efficacy of cell implantation via 3D-spheroids to treat basal tone in fecal incontinence remains unclear. To address this, in this study, we aimed to identify cell differentiation and assess the development of a contractile phenotype corresponding to smooth muscle cells (SMCs) following implantation of 3D-spheroid and 2D-cultured human adipose stem cells (hASCs) in an in vivo internal anal sphincter (IAS)-targeted mouse model. Methods: We developed an IAS-targeted in vivo model via rapid freezing (at − 196 °C) of the dorsal layers of the region of interest (ROI) of the IAS ring posterior quarter, between the submucosal and muscular layers, following submucosal dissection (n = 60 rats). After implantation of tetramethylindocarbocyanine perchlorate (Dil)-stained 3D and 2D-cells into randomly allocated cryoinjured rats, the entire sphincter ring or only the cryoinjured ROI was harvested. Expression of SMC markers, RhoA/ROCKII and its downstream molecules, and fibrosis markers was analyzed. Dil, α-smooth muscle actin (α-SMA), and RhoA signals were used for cell tracking. Results: In vitro, 3D-spheroids exhibited higher levels of SMC markers and RhoA/ROCKII-downstream molecules than 2D-hASCs. The IAS-targeted cryoinjured model exhibited substantial loss of SMC layers of the squamous epithelium lining of the anal canal, as well as reduced expression of SMC markers and RhoA-related downstream molecules. In vivo, 3D-spheroid implantation induced SMC markers and contractile molecules weakly at 1 week. At 2 weeks, the mRNA expression of aSma, Sm22a, Smoothelin, RhoA, Mypt1, Mlc20, Cpi17, and Pp1cd increased, whereas that of fibrosis markers reduced significantly in the 3D-spheroid implanted group compared to those in the sham, non-implanted, and 2D-hASC implanted groups. Protein levels of RhoA, p-MYPT1, and p-MLC20 were higher in the 3D-spheroid-implanted group than in the other groups. At 2 weeks, in the implanted groups, the cryoinjured tissues (which exhibited Dil, α-SMA, and RhoA signals) were restored, while they remained defective in the sham and non-implanted groups. Conclusions: These findings demonstrate that, compared to 2D-cultured hASCs, 3D-spheroids more effectively induce a contractile phenotype that is initially weak but subsequently improves, inducing expression of RhoA/ROCKII-downstream molecules and SMC differentiation associated with IAS basal tone. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is increasing globally, with approximately 700 million obese people worldwide. Currently, regulating energy homeostasis by increasing energy expenditure is attracting attention as a strategy for treating obesity. White adipose tissue is known to play a role in accumulating energy by storing excess energy, while brown adipose tissue expends energy and maintains body temperature. Thus, the browning of white adipose tissue has been shown to be effective in controlling obesity. Hedera helix (H. helix) has been widely used as a traditional medicine for various diseases. In several previous studies, hederagenin (HDG) from H. helix has demonstrated many biological activities. In this study, we investigated the antiobesity effect of HDG on fat browning in 3T3-L1 adipocytes. Consequent to HDG treatment, a reduction in lipid accumulation was measured through oil red O staining. In addition, this study investigated that HDG increases energy expenditure by upregulating the expression of several targets related to thermogenesis, including uncoupling protein 1 (UCP1). This process involves inhibiting lipogenesis via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and promoting lipolysis through the protein kinase A (PKA) pathway. HDG is expected to be effective in promoting fat browning, indicating its potential as a natural antiobesity candidate. [ABSTRACT FROM AUTHOR]

Unabated 21st-century climate change will accelerate Arctic-Subarctic permafrost thaw which can intensify microbial degradation of carbon-rich soils, methane emissions, and global warming. The impact of permafrost thaw on future Arctic-Subarctic wildfires and the associated release of greenhouse gases and aerosols is less well understood. Here we present a comprehensive analysis of the effect of future permafrost thaw on land surface processes in the Arctic-Subarctic region using the CESM2 large ensemble forced by the SSP3-7.0 greenhouse gas emission scenario. Analyzing 50 greenhouse warming simulations, which capture the coupling between permafrost, hydrology, and atmosphere, we find that projected rapid permafrost thaw leads to massive soil drying, surface warming, and reduction of relative humidity over the Arctic-Subarctic region. These combined processes lead to nonlinear late-21st-century regime shifts in the coupled soil-hydrology system and rapid intensification of wildfires in western Siberia and Canada. In a warming world, future rapid permafrost thawing can cause significant soil drying, surface warming, and atmospheric drying in the Arctic-Subarctic region, leading to an intensification of peat and forest fires in western Siberia and Canada. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a disease caused by mutations in DNA differentiating cancer cells from normal cells. Precision medicine could exploit these genetic differences to identify and create therapeutic opportunities that selectively kill cancer cells while sparing normal cells. In some cancers, the same mutations recur, making them desirable biomarkers for genetics-based therapeutic strategies. This is the case for the gene ARID1A which is lost in about 50% of ovarian clear cell carcinomas. We used genetic screening to identify targets for killing an ovarian clear cell carcinoma cell line lacking the ARID1A gene. We identified a cancer stress response regulator called KEAP1 as a potential target for ARID1A-deficient ovarian clear cell carcinomas. Using different approaches and cell lines, we observed a relationship where ARID1A-deficient cells required KEAP1 for fitness. Together these data suggest that KEAP1 could be pursued as a means to selectively kill certain types of ARID1A-deficient cancer. ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells. [ABSTRACT FROM AUTHOR]

As cellular senescence, reactive oxygen species (ROS) accumulate excessively, causing cellular damage. Flavonoids derived from natural products are known for their antioxidant effects and their ability to delay cellular senescence. Previous studies have attempted to mitigate cellular senescence using flavonoids from natural sources. However, the detailed mechanisms and regulatory targets of some flavonoids exhibiting antioxidant effects have not been fully elucidated. Therefore, we screened a library of flavonoids for antioxidant properties. Isoschaftoside, a glycosidic flavonoid, significantly reduced ROS levels in senescent cells. It was found that mitochondrial function was restored, and dependence on glycolysis was reduced in senescent cells treated with isoschaftoside. Additionally, we identified that isoschaftoside suppresses ROS by reducing the expression of RAC2 and LINC00294 in senescent cells. Taken together, this study establishes a novel mechanism for ROS inhibition and the regulation of cellular senescence by isoschaftoside. Our findings contribute important insights to antioxidant and anti-senescence research. [ABSTRACT FROM AUTHOR]

Simple Summary: Many tick species pose a threat to public health by transmitting diseases to humans and animals. Haemaphysalis longicornis (The Asian longhorned tick) is known to be the main vector that transmits severe fever with thrombocytopenia syndrome virus. In the United States, it was first identified in New Jersey during 2017 on domestic sheep. Even though H. longicornis is an important vector, research on its major activity period is lacking. Tick activity patterns may vary depending on climate factors, the host, and region. This study aimed to survey the patterns of diel activity in H. longicornis and the potential effects of climatic factors on tick activity. The highest activity occurred at 10:00 to 14:00. Avoiding the times of highest activity is considered the best way to reduce contact with ticks. Haemaphysalis longicornis is one of the most medically important carriers of various pathogens. Although H. longicornis is an important vector, only basic ecological and biological information has been obtained, primarily focusing on its abundance and distribution. This study determined the most active time and meteorological conditions for the diel activity of H. longicornis. The diel activity pattern of H. longicornis was the highest between 10:00 and 14:00, and the lowest between 22:00 and 02:00. The major activity temperature of H. longicornis was between 25 °C and 40 °C, with the highest activity at 35 °C. The relative humidity was between 30% and 70% during the active period. Temperature had the highest correlation with diel activity (R = 0.679), followed by humidity (R = −0.649) and light intensity (R = 0.572). Our results provide basic information for the development of tick-borne disease vector control programs and tick surveillance. [ABSTRACT FROM AUTHOR]

Objectives: Hypersensitive acupoints in specific body areas are associated with corresponding internal or visceral disorders. Back-shu points are clinically significant for the diagnosis of visceral organ disease, according to the biomechanical characteristics of the acupoints. In this study, we assessed the biomechanical characteristics and pain sensitivities of five back-shu points linked to five visceral organs in healthy participants. Methods: The study included 48 volunteer participants. A myotonometry was used to assess muscle tone and muscle stiffness at five back-shu points associated with visceral organs. Pressure was monitored using a microcontroller and a force sensor. Pain sensitivity was assessed in response to deep pressure pain produced by a constant force. Results: Substantial differences in muscle tone and stiffness were observed at the five back-shu points; muscle tone was highest at BL15, whereas muscle tone and muscle stiffness were lowest at BL23. Moreover, pain sensitivity was significantly different among the acupoints; pain sensitivity was highest at BL23. There was a significant negative correlation between muscle tone and pain sensitivity. Conclusions: We found significant differences in muscle tone, muscle stiffness, and pain sensitivity among five back-shu points associated with visceral organs, which may be attributable to anatomical variations at each point. Our findings suggest that differences at back-shu points should be considered to ensure the accurate diagnosis of visceral disease. [ABSTRACT FROM AUTHOR]