It has been shown that nuclear expression of S100A4 is significantly correlated with increased metastasis and reduced survival in patients with gastric cancer and many other cancers. However, the ...factors which could influence the nuclear contents of S100A4 in cancer cells are not clear. It has also been reported that Interleukin‐1β (IL‐1β) promotes the nuclear translocation of S100A4 in chondrocytes. Previous studies have shown that IL‐1β promotes the stemness of colon cancer cells, and S100A4 is also involved in maintaining cancer‐initiating cells in head and neck cancers. We speculate that IL‐1β might promote the nuclear translocation of S100A4 protein in MGC803 gastric cancer cells and therefore enhance their stem‐like properties. The results from Western‐blot and qRT‐PCR analysis showed that IL‐1β increased the nuclear and total cellular content of S100A4 protein and S100A4 mRNA level in MGC803 cells. LY294002, a pharmacological inhibitor of Phosphoinositide 3‐kinase (PI3K) reversed the above effects. Functional studies indicated that IL‐1β promoted the colony‐forming and spheroid‐forming capabilities of the cells and the expression of SOX2 and NANOG gene. PI3K or S100A4 inhibition reversed the IL‐1β‐mediated increase in colony and spheroid‐forming capabilities of the cells. LY294002 also reversed the elevated SOX2 and NANOG expression induced by IL‐1β. Our study demonstrated that IL‐1β promote the nuclear translocation of S100A4 protein in gastric cancer cells MGC803, which are PI3K dependent, suggesting the existence of IL‐1β‐PI3K‐S100A4 pathway for the first time. The study also showed that IL‐1β promoted stem‐like properties of the cells through the new pathway.
This study suggests the existence of a new IL‐1β‐PI3K‐S100A4 pathway, which promotes the stem‐like properties of gastric cancer cells, providing new clues for the diagnosis, and treatment of gastric cancer.
Marine chlorophyll a is a key molecule for photosynthesis of marine plants and some plankton, which is important in marine ecosystems. This study utilized the chlorophyll a concentration data product ...observed by the MODIS sensor (MODerate resolution Imaging Spectroradiometer) to construct a long-term sequence of chlorophyll a concentration dataset by processing the raw data. Based on this, the multi-time-scale chlorophyll a concentration data was synthesized, and it was used to analyze the spatial and temporal variation characteristics of chlorophyll a concentration in China Seas. In addition, several oceanographic variables, including sea surface temperature, nutrients (phosphate, nitrate, silicate), partial pressure of seawater carbon dioxide, net primary productivity of the ocean, physical dynamics of seawater processes (mixed layer), were analyzed to ascertain their potential influence on chlorophyll a concentration. Finally, we analyzed the effects of changes in chlorophyll a concentration on marine fisheries. The result showed that: The average value of chlorophyll a concentration in China Seas from 2002 to 2022 was 0.874 mg/m
3
, with the highest concentration observed in the Bohai Sea area (4.547 mg/m
3
) and the lowest in the South China Sea area (0.288 mg/m
3
). The spatial variation of chlorophyll a concentration revealed an overall decrease of 0.0095 mg/m
3
in China Seas from 2002 to 2022. From the perspective of time changes, the concentration of chlorophyll a in China’s Bohai Sea area showed a downward trend from 2002 to 2022, while the Yellow Sea area showed an upward trend. The concentration remained relatively stable in the East China Sea area, whereas a significant declining trend was observed in the South China Sea area. The relationship between temperature and chlorophyll a concentration was non-linear, and chlorophyll a concentration showed some fluctuation or threshold effect with the change of seawater temperature. The three nutrient salts studied have a promoting effect on chlorophyll a, among which phosphate has the most obvious promoting effect on chlorophyll a. Chlorophyll a was negatively correlated with pCO
2
and positively correlated with ocean net primary productivity. Seasonal changes in the mixed layer had a significant effect on changes in the upper marine nutrients, which in turn affected changes in chlorophyll a concentration. Six of the eight types of algae studied show a trend toward deeper sea depths, which may have implications for the food availability of marine fish at different levels and pose new challenges for marine fisheries development.
Detachment from the extracellular matrix induces a form of programmed cell death termed anoikis. Resistance to anoikis permits cancer cells to survive in systemic circulation and facilitates their ...metastasis to distant organs. It is well known that S100A4 is overexpressed in many tumors and involved in tumor metastasis, but the mechanisms of the metastasis‐promoting function of S100A4 are not fully understood. We hypothesized that S100A4 might play a role in anoikis of gastric cancer cells and further affects their metastasis. To test this hypothesis, we changed the expression of S100A4 by means of RNA interference or experimental overexpression and investigated the effect on anoikis. We found that knockdown of S100A4 by RNA interference led to significantly increased anoikis, whereas overexpression of S100A4 resulted in inhibition of anoikis. Furthermore, we provide evidence that inhibition of S100A4 resulted in the downregulation of α5 and αv integrin expression. These findings suggest that S100A4 protects gastric cancer cells from anoikis by regulation of αv and α5 integrin expression, which sheds a novel light for the role of S100A4 in cancer metastasis. (Cancer Sci 2011; 102: 1014–1018)
Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) ...antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro3.4octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.
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•Structure-based scaffold hopping to design a series of sigma-1 receptor antagonists.•σ1R antagonists harboring the 2,6-diazaspiro3.4octan-7-one scaffold are easily synthesized and showed high potence.•Compound 32 significantly enhanced the antinociceptive effect of morphine.•Compound 32 can rescue morphine-induced analgesic tolerance.
Abstract
Inferring the geographic mode of speciation is essential for explaining the generation and assembly of biodiversity, but has been rarely applied to the temperate flora of China. Fagus ...longipetiolata and F. lucida are a sister pair of beech species with largely overlapping ranges in subtropical China, however, little is known about the geographic mode of speciation and the formation of their sympatric distributions. In this study, we used IMa2 and fastsimcoal2 to simulate the speciation history of the two sisters. On the basis of 11 nuclear loci screened for 27 populations/species, their divergence time was estimated to 8.37 Mya by IMa2, and weak interspecific gene flow was detected. The simulation by fastsimcoal2 found that F. longipetiolata and F. lucida diverged ~8.53 Mya, then came into contact and hybridized at 0.8 Mya. The extended Bayesian skyline plots indicated that F. lucida began demographic expansion prior to the Pleistocene at 3 Mya, whereas F. longipetiolata increased its effective population size during the Quaternary, between 0.8 and 0.5 Mya. Ecological niche analysis and niche modelling showed that the two beeches had subtle niche differentiation and their projected distributions were largely overlapped across the late Quaternary. These results, coupled with well-studied fossil records in Fagus, demonstrate that these two beech species diverged allopatrically at the high latitudes of the Northern Hemisphere, and came into contact and hybridized with each other after successive migrations into subtropical (i.e. warm temperate) China recently. However, the two beeches may have developed strong intrinsic reproductive barriers due to long-term allopatry, allowing them to coexist in subtropical China. Our results illuminate the assembly history of the temperate woody flora in subtropical China, supporting that many relict temperate lineages in subtropical China may have established their populations recently.
Angiotensin receptor-neprilysin inhibitor (ARNi), comprised of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has established itself as a safe and effective intervention for ...hypertension. S086 is a novel ARNi cocrystal developed by Salubris for the treatment of heart failure and hypertension.
Dahl Salt Sensitive (DSS) hypertensive rat model and telemetry system were employed in this study to investigate the anti-hypertensive efficacy of S086 and compare it with the first ARNi-LCZ696.
The study showed that oral administration of S086 dose-dependently lowered blood pressure (
< 0.001). The middle dosage of S086 (23 mg/kg) exhibited efficacy comparable to LCZ696 (68 mg/kg), while also demonstrating superiority at specific time points (
< 0.05). Notably, water consumption slightly decreased post-treatment compared to the vehicle group. Furthermore, there were significant increases in natriuresis and diuresis observed on the first day of treatment with 23 mg/kg and 68 mg/kg S086 (
< 0.001). However, over the course of treatment, the effects in all treatment groups gradually diminished. This study demonstrates the anti-hypertensive efficacy of S086 in DSS hypertensive rat model, offering promising avenues for the clinical development of S086 as a hypertension treatment.
OBJECTIVE: To investigate the use of non-contrast-enhanced (NCE) and contrast-enhanced (CE) CT radiomics signatures (Rad-scores) as prognostic factors to help improve the prediction of the overall ...survival (OS) of postoperative colorectal cancer (CRC) patients. METHODS: A retrospective analysis was performed on 65 CRC patients who underwent surgical resection in our hospital as the training set, and 19 patient images retrieved from The Cancer Imaging Archive (TCIA) as the external validation set. In training, radiomics features were extracted from the preoperative NCE/CE-CT, then selected through 5-fold cross validation LASSO Cox method and used to construct Rad-scores. Models derived from Rad-scores and clinical factors were constructed and compared. Kaplan-Meier analyses were also used to compare the survival probability between the high- and low-risk Rad-score groups. Finally, a nomogram was developed to predict the OS. RESULTS: In training, a clinical model achieved a C-index of 0.796 (95% CI: 0.722–0.870), while clinical and two Rad-scores combined model performed the best, achieving a C-index of 0.821 (95% CI: 0.743–0.899). Furthermore, the models with the CE-CT Rad-score yielded slightly better performance than that of NCE-CT in training. For the combined model with CE-CT Rad-scores, a C-index of 0.818 (95% CI: 0.742–0.894) and 0.774 (95% CI: 0.556–0.992) were achieved in both the training and validation sets. Kaplan-Meier analysis demonstrated a significant difference in survival probability between the high- and low-risk groups. Finally, the areas under the receiver operating characteristics (ROC) curves for the model were 0.904, 0.777, and 0.843 for 1, 3, and 5-year survival, respectively. CONCLUSION: NCE-CT or CE-CT radiomics and clinical combined models can predict the OS for CRC patients, and both Rad-scores are recommended to be included when available.
NaZn13-type La(Fe,Si)13 alloys are one of the most promising magnetocaloric materials for room-temperature magnetic refrigeration. However, the narrow ferromagnetic-to-paramagnetic transition ...temperature range of La(Fe,Si)13 alloys severely limited their magnetic refrigeration application. Herein, a series of La1.4Fe11.8-xCoxSi1.2 (x = 0.88, 0.94, 0.98, 1.02, 1.06) alloys were designed and prepared by high-energy ball milling and annealing. It is discovered that all the samples are composed of La(Fe,Co,Si)13 main phase and a small amount of α-Fe phase. The Curie temperature of the ferromagnetic-to-paramagnetic transition was well adjusted to room temperature by optimizing the x. A maximum magnetic entropy change (-ΔSM) of 4.0 J kg−1 K−1 for the sample with x = 0.98 was obtained at a magnetic field of 2 T. Meanwhile, all the samples exhibit a significant increase in the half-height width of -ΔSM reaching approximately 35 K, increased by more than 41% compared with that of the reference sample prepared by arc melting. The broadened temperature range originates from the lattice distortion induced by the ball milling process. Our work indicates that La(Fe,Si)13 alloys with relatively large -ΔSM and wide transition temperature range can be simultaneously obtained around room temperature by optimizing the composition and the ball milling process.
•A series of La1.4Fe11.8-xCoxSi1.2 alloys were prepared by the high-energy ball milling and annealing treatment.•The -ΔSM of the sample with x = 0.98 reaches 4.0 J kg−1 K−1 around the room temperature under a magnetic field of 2 T.•All the samples exhibit a significant increase in δTFWHM reaching approximately 35 K due to the lattice distortion induced by the ball milling.
Flavonoids are important bioactive components in Dendrobium officinale, a medicinal orchid. They are involved in many biological activities, including protecting plants against biotic and abiotic ...stresses. Research on the key genes related to flavonoid biosynthesis in D. officinale is limited. In this study, one of the key flavonoid biosynthesis genes, flavanone 3-hydroxylase (F3H), was characterized from D. officinale. The open reading frame of DoF3H was 1 134 bp long and it encoded a 377-amino acid protein. The DoF3H protein showed considerably high homology with F3H proteins from other plant species and shared a common evolutionary ancestor with other F3Hs. DoF3H transcripts were detected in different organs of adult plants and mainly accumulated in flowers, followed by roots, stems and leaves, a pattern that was similar to the content of flavonoids. Recombinant DoF3H protein, which was localized in the cytosol, could convert naringenin to dihydrokaempferol. The mRNA levels of DoF3H were significantly induced by salt and cold stresses. Furthermore, the heterologous expression of DoF3H in Escherichia coli conferred it higher tolerance to salt and cold stresses. These results provide insight into the molecular function of DoF3H in the biosynthesis of flavonoids, and provide a new application for improvement of abiotic tolerance in D. officinale.
Early detection of visual impairment is crucial but is frequently missed in young children, who are capable of only limited cooperation with standard vision tests. Although certain features of ...visually impaired children, such as facial appearance and ocular movements, can assist ophthalmic practice, applying these features to real-world screening remains challenging. Here, we present a mobile health (mHealth) system, the smartphone-based Apollo Infant Sight (AIS), which identifies visually impaired children with any of 16 ophthalmic disorders by recording and analyzing their gazing behaviors and facial features under visual stimuli. Videos from 3,652 children (≤48 months in age; 54.5% boys) were prospectively collected to develop and validate this system. For detecting visual impairment, AIS achieved an area under the receiver operating curve (AUC) of 0.940 in an internal validation set and an AUC of 0.843 in an external validation set collected in multiple ophthalmology clinics across China. In a further test of AIS for at-home implementation by untrained parents or caregivers using their smartphones, the system was able to adapt to different testing conditions and achieved an AUC of 0.859. This mHealth system has the potential to be used by healthcare professionals, parents and caregivers for identifying young children with visual impairment across a wide range of ophthalmic disorders.
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