Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered ...principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high‐throughput screening based on myelin basic protein expression using neural progenitor cells‐derived OPCs has been performed and, PD0325901—an MEK (MAPK kinase) inhibitor—is found to significantly enhance OPC to OL differentiation in a dose‐ and time‐dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK–ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC–neuron co‐culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone‐induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK–ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.
Main Points
MEK inhibitors, represented by PD0325901, promote oligodendrocyte generation.
PD0325901 promotes myelin formation both in vitro and in vivo.
The MAPK‐ERK pathway might be an intriguing target to develop new therapies for demyelinating diseases.
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great potential in applications such as regenerative medicine, cardiac disease modeling, and
drug evaluation. However, hPSC-CMs are ...immature, which limits their applications. During development, the maturation of CMs is accompanied by a decline in their proliferative capacity. This phenomenon suggests that regulating the cell cycle may facilitate the maturation of hPSC-CMs. Aurora kinases are essential kinases that regulate the cell cycle, the role of which is not well studied in hPSC-CM maturation. Here, we demonstrate that CYC116, an inhibitor of Aurora kinases, significantly promotes the maturation of CMs derived from both human embryonic stem cells (H1 and H9) and iPSCs (induced PSCs) (UC013), resulting in increased expression of genes related to cardiomyocyte function, better organization of the sarcomere, increased sarcomere length, increased number of mitochondria, and enhanced physiological function of the cells. In addition, a number of other Aurora kinase inhibitors have also been found to promote the maturation of hPSC-CMs. Our data suggest that blocking aurora kinase activity and regulating cell cycle progression may promote the maturation of hPSC-CMs.
Low-permeability reservoirs have tiny pores with winding and complicated pore throats. The oil recovery efficiency of low-permeability reservoirs can be enhanced through the displacement of reservoir ...oil through imbibition. In the present study, experiments were conducted to investigate variations in the imbibition height of hydrophilic and weakly-hydrophilic rock samples under different interfacial tensions. An imbibition model considering imbibition resistance and bending of pore throats was established based on fractal theory. According to the experimental results, variations in the imbibition height of low-permeability rock samples with time can be divided into three stages. In the first stage, the capillary force plays a dominant role, while the viscous force and gravity have very slight effects. The imbibition height first increases rapidly and then levels off to a constant rate. With the increase in interfacial tension, the imbibition rate in the first stage increases, the ultimate imbibition height increases initially and then decreases, and the contribution of the imbibition height in the first stage to the ultimate imbibition height becomes greater. There is an optimal interfacial tension that causes the ultimate imbibition height to reach its maximum. The calculated results obtained from the proposed imbibition model are consistent with the experimental results, indicating that the model can accurately reflect the change in the imbibition height in low-permeability reservoirs in the first stage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Anaerobic methanotrophic (ANME) archaea can drive anaerobic oxidation of methane (AOM) using solid iron or manganese oxides as the electron acceptors, hypothetically
direct extracellular electron ...transfer (EET). This study investigated the response of
"
TS" (type strain), an ANME archaeon previously characterized to perform nitrate-dependent AOM, to an Fe(III)-amended condition over a prolonged period. Simultaneous consumption of methane and production of dissolved Fe(II) were observed for more than 500 days in the presence of
"
TS," indicating that this archaeon can carry out Fe(III)-dependent AOM for a long period.
"
TS" possesses multiple multiheme
-type cytochromes (MHCs), suggesting that it may have the capability to reduce Fe(III)
EET. Intriguingly, most of these MHCs are orthologous to those identified in
"
," an Fe(III)-reducing ANME archaeon. In contrast, the population of
"
TS" declined and was eventually replaced by
"
," implying niche differentiation between these two ANME archaea in the environment.
Objective:
We aimed to investigate the effects of exercise, monitored and managed using smart bracelets, on body composition, and quality of life in breast cancer survivors.
Methods:
A ...before-and-after study was conducted in 109 patients who were in the recovery phase of breast cancer and attended the Breast Surgery Department of the Cancer Hospital of Fudan University up to December 2017. Patients were advised to adhere to at least 150 minutes of moderate-intensity exercise per week, and a smart bracelet was issued to each participant to record their daily exercise data for 3 months. Bioelectrical impedance analysis was used to observe the effects of short-term unsupervised exercise intervention on body composition in patients recovering from breast cancer. Patients completed the Functional Assessment of Cancer Therapy-Breast to assess health-related quality of life.
Results:
Weight, body mass index (BMI), body fat mass (BFM), fat mass index (FMI), percent body fat (PBF), arm circumference (AC), arm muscle circumference (AMC), and visceral fat area (VFA) were lower than baseline after exercising for 3 months based on data from the wearable devices (P < .05). The only significant improvement was found in the “additional concerns about breast cancer” category among the quality-of-life assessments (P < .05). The average walking time was negatively associated with BFM, PBF, and FMI, while the average calorie consumption due to running was positively associated with fat free mass (FFM).
Conclusion:
In this study, we demonstrated that short-term exercise may be beneficial for postoperative breast cancer survivors. A wearable device could help patients track physical data easily and promote a healthier and more positive life.
Hepatocyte transplantation has emerged as a possible treatment option for end-stage liver disease. However, an important obstacle to therapeutic success is the low level of engraftment and ...proliferation of transplanted hepatocytes, which do not survive long enough to exert therapeutic effects. Thus, we aimed to explore the mechanisms of hepatocyte proliferation in vivo and find a way to promote the growth of transplanted hepatocytes.
Hepatocyte transplantation was performed in Fah-/- mice to explore the mechanisms of hepatocyte proliferation in vivo. Guided by in vivo regeneration mechanisms, we identified compounds that promote hepatocyte proliferation in vitro. The in vivo effects of these compounds on transplanted hepatocytes were then evaluated.
The transplanted mature hepatocytes were found to dedifferentiate into hepatic progenitor cells (HPCs), which proliferate and then convert back to a mature state at the completion of liver repopulation. The combination of two small molecules Y-27632 (Y, ROCK inhibitor) and CHIR99021 (C, Wnt agonist) could convert mouse primary hepatocytes into HPCs, which could be passaged for more than 30 passages in vitro. Moreover, YC could stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs. Netarsudil (N) and LY2090314 (L), two clinically used drugs which target the same pathways as YC, could also promote hepatocyte proliferation in vitro and in vivo, by facilitating HPC conversion.
Our work suggests drugs promoting hepatocyte dedifferentiation may facilitate the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy.
Hepatocyte transplantation may be a treatment option for patients with end-stage liver disease. However, one important obstacle to hepatocyte therapy is the low level of engraftment and proliferation of the transplanted hepatocytes. Herein, we show that small molecule compounds which promote hepatocyte proliferation in vitro by facilitating dedifferentiation, could promote the growth of transplanted hepatocytes in vivo and may facilitate the application of hepatocyte therapy.
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•Transplanted hepatocytes dedifferentiate into HPCs before repopulation.•Y-27632 (Y) and CHIR99021 (C) convert mouse hepatocytes into HPCs & support long-term culture (>30 passages) in vitro.•YC stimulate the proliferation of transplanted hepatocytes in Fah-/- livers by promoting their conversion into HPCs.•Two clinically used drugs target the same pathways as YC, also promoting hepatocyte proliferation in vitro and in vivo.
Stomata are key innovation in plants that drives the global carbon and water cycle. In the past few decades, many stomatal models have been developed for studying gas exchange, photosynthesis, and ...transpirational characteristics of plants, but they provide limited information on stomatal mechanisms at the molecular and cellular levels. Quantitative mathematical modeling offers an effective
approach to explore the link between microscopic transporter functioning and the macroscopic stomatal characteristics. As a first step, a dynamic system model based on the guard cell membrane transport system was developed and encoded in the OnGuard software. This software has already generated a wealth of testable predictions and outcomes sufficient to guide phenotypic and mutational studies. It has a user-friendly interface, which can be easily accessed by researchers to manipulate the key elements and parameters in the system for guard cell simulation in plants. To promote the adoption of this OnGuard application, here we outline a standard protocol that will enable users with experience in basic plant physiology, cell biology, and membrane transport to advance quickly in learning to use it.
Methane is an abundant low-carbon fuel that provides a valuable energy resource, but it is also a potent greenhouse gas. Therefore, anaerobic oxidation of methane (AOM) is an essential process with ...central features in controlling the carbon cycle.
'Methanoperedens nitroreducens'
is a recently discovered methanotrophic archaeon capable of performing AOM via a reverse methanogenesis pathway utilizing nitrate as the terminal electron acceptor. Recently, reverse methanogenic pathways and energy metabolism among anaerobic methane-oxidizing archaea (ANME) have gained significant interest. However, the energetics and the mechanism for electron transport in nitrate-dependent AOM performed by
is unclear. This paper presents a genome-scale metabolic model of
,
MN22HE, which contains 813 reactions and 684 metabolites. The model describes its cellular metabolism and can quantitatively predict its growth phenotypes. The essentiality of the cytoplasmic heterodisulfide reductase HdrABC in the reverse methanogenesis pathway is examined by modeling the electron transfer direction and the specific energy-coupling mechanism. Furthermore, based on better understanding electron transport by modeling, a new energy transfer mechanism is suggested. The new mechanism involves reactions capable of driving the endergonic reactions in nitrate-dependent AOM, including the step reactions in reverse canonical methanogenesis and the novel electron-confurcating reaction HdrABC. The genome metabolic model not only provides an in silico tool for understanding the fundamental metabolism of ANME but also helps to better understand the reverse methanogenesis energetics and its thermodynamic feasibility.
Hydraulic fracturing is one of the key technologies to enhance the oil recovery from tight sandstone reservoirs. The study on the behavior of imbibition for tight sandstone reservoir is of great ...significance to increase oil production after fracturing. In this paper, nuclear magnetic resonance (NMR) and high-pressure mercury injection were implemented on the samples taken from the Yanchang Formation of the Ordos Basin. The NMR T 2 curves of the core at the state of 100% water saturated were converted to pore-throat radius distribution curves. On this basis, the experiments of imbibition and displacement were conducted and the changes of fluid distribution, imbibition quantity, and imbibition rate with different scale pores and different imbibition times were analyzed. Moreover, the results of imbibition and displacement were compared to assess the distribution of the recoverable and remaining oil under two exploitation modes and the contribution of imbibition made to displacement in pores at different scales. The result shows that imbibition is a relatively slow process. The entire imbibition process is mainly affected by nanopores, which are widely distributed in cores, and the imbibition rate of total pores constantly decreases as the imbibition time increases. Moreover, the relative recovery in pores at different scales shows a huge difference under the two exploitation modes of imbibition and displacement. During imbibition, smaller pores produced higher degrees of oil, while during displacement, larger pores have higher relative recovery. The contribution of imbibition made to displacement in nanopores was the highest and decreased with the increase of the pore-throat size.
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