Significance The conventional parametric approach to modeling relies on hypothesized equations to approximate mechanistic processes. Although there are known limitations in using an assumed set of ...equations, parametric models remain widely used to test for interactions, make predictions, and guide management decisions. Here, we show that these objectives are better addressed using an alternative equation-free approach, empirical dynamic modeling (EDM). Applied to Fraser River sockeye salmon, EDM models ( i ) recover the mechanistic relationship between the environment and population biology that fisheries models dismiss as insignificant, ( ii ) produce significantly better forecasts compared with contemporary fisheries models, and ( iii ) explicitly link control parameters (spawning abundance) and ecosystem objectives (future recruitment), producing models that are suitable for current management frameworks.
It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon ( Oncorhynchus nerka ) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner–recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background. Neoadjuvant immunotherapy is promising for locally advanced non-small-cell lung cancer (NSCLC). The in situ immune patterns, as a predictor of PD-1/PD-L1 blockade outcomes, of the primary ...tumor (PT) and metastatic lymph nodes (mLNs) are unknown. Methods. Multiplex immunofluorescence staining and multispectral imaging were used to evaluate the in situ immune patterns of T cells (CD3+) and cytotoxic T cells (CD8+) in terms of density, location (center of tumor (CT) and invasive margin (IM)), and the PD-L1 expression status of tumor cells and stromal T cells of paired PTs and mLNs in 38 stage III NSCLCs. Results. The densities of T cells and cytotoxic T cells were correlated between PTs and mLNs at both CT and IM. Higher densities of stromal T cells (S-CD3+) at CT and both S-CD3+ and cytotoxic T cells (S-CD8+) at IM were observed in mLNs compared to PTs, while in tumor compartment, there were no differences in the densities of T cells (T-CD3+) or cytotoxic T cells (T-CD8+). Only the density of stromal PD-L1-positive T cells (S-PD-L1+CD3+) at CT was correlated between PTs and mLNs, while the densities and frequencies of S-PD-L1+CD3+ at CT and IM of mLNs were higher than PTs. Combining positive score discordance of PD-L1 between PTs and mLNs was greater than tumor proportion score. Conclusions. In situ immune patterns of T cells and cytotoxic T cells were different between PTs and mLNs in NSCLC. The heterogeneity of the in situ immune patterns may result in different immune-mediated responses to neoadjuvant immunotherapy in PT and mLNs.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Chilling tolerance was increased in seed germination and root growth of wheat seedlings grown in media containing 20 µg/mL cerebroside C (CC), isolated from the endophytic Phyllosticta sp. TG78. ...Seeds treated with 20 µg/mL CC at 4 °C expressed the higher germination rate (77.78%), potential (23.46%), index (3.44) and the shorter germination time (6.19 d); root growth was also significantly improved by 13.76% in length, 13.44% in fresh weight and 6.88% in dry mass compared to controls. During the cultivation process at 4 °C for three days and the followed 24 h at 25 °C, lipid peroxidation, expressed by malondialdehyde (MDA) content and relative membrane permeability (RMP) was significantly reduced in CC-treated roots; activities of lipoxygenase (LOX), phospholipid C (PLC) and phospholipid D (PLD) were inhibited by 13.62-62.26%, 13.54-63.93% and 13.90-61.17%, respectively; unsaturation degree of fatty acids was enhanced through detecting the contents of CC-induced linoleic acid, linolenic acid, palmitic acid and stearic acid using GC-MS; capacities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were individually increased by 7.69-46.06%, 3.37-37.96%, and -7.00-178.07%. These results suggest that increased chilling tolerance may be due, in part, to the reduction of lipid peroxidation and alternation of lipid composition of roots in the presence of CC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drugs with similar side-effect profiles may share similar therapeutic properties through related mechanisms of action. In this study, a drug-drug network was constructed based on the similarities ...between their clinical side effects. The indications of a drug may be inferred by the enriched FDA-approved functions of its neighbouring drugs in the network. We systematically screened new indications for 1234 drugs with more than 2 network neighbours, 36.87% of the drugs achieved a performance score of Normalized Discounted Cumulative Gain in the top 5 positions (NDCG@5) ≥ 0.7, which means most of the known FDA-approved indications were well predicted at the top 5 positions. In particular, drugs for diabetes, obesity, laxatives and antimycobacterials had extremely high performance with more than 80% of them achieving NDCG@5 ≥ 0.7. Additionally, by manually checking the predicted 1858 drug-indication pairs with Expression Analysis Systematic Explorer (EASE) score ≤ 10(-5) (EASE score is a rigorously modified Fisher exact test p value), we found that 80.73% of such pairs could be verified by preclinical/clinical studies or scientific literature. Furthermore, our method could be extended to predict drugs not covered in the network. We took 98 external drugs not covered in the network as the test sample set. Based on our similarity criteria using side effects, we identified 41 drugs with significant similarities to other drugs in the network. Among them, 36.59% of the drugs achieved NDCG@5 ≥ 0.7. In all of the 106 drug-indication pairs with an EASE score ≤ 0.05, 50.94% of them are supported by FDA approval or preclinical/clinical studies. In summary, our method which is based on the indications enriched by network neighbors may provide new clues for drug repositioning using side effects.
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Background & Aims
Hepatocellular carcinoma (HCC) is one of the leading causes of tumour‐related death. Here, we investigated the molecular mechanism of HCC by studying the function of circ_GLIS2.
...Methods
Human HCC specimens and cell lines were used. Sanger sequencing, actinomycin D and RNase R treatment were performed to validate circular RNA features of circ_GLIS2. qRT‐PCR, western blotting, immunostaining, and IHC were employed to examine levels of circ_GLIS2, GLIS2 mRNA, and EMT‐related markers. CCK‐8, colony formation, flow cytometry, wound healing assay, and transwell assays were performed to evaluate cancer cell proliferation, apoptosis, migration, and invasion. RIP and RNA pull‐down assay were used to validate EIF4A3/GLIS2 mRNA interaction. MSP was performed to measure the methylation status of GLIS2 promoter. Nude mouse xenograft model was used to examine tumour growth and metastasis in vivo.
Results
Circ_GLIS2 and linear GLIS2 mRNA were reduced in human HCC tissues and cells. Their low levels correlated with a poor survival rate of HCC patients. Overexpression of circ_GLIS2 and GLIS2 suppressed HCC cell proliferation, migration, and invasion but promoted cell apoptosis. GLIS2 promoter region was hypermethylated in HCC cells. EIF4A3 was directly bound with GLIS2 mRNA and promoted circ_GLIS2/GLIS2 expression. Moreover, overexpression of circ_GLIS2 restrained HCC tumour growth and metastasis in vivo.
Conclusion
Circ_GLIS2 suppresses HCC growth and metastasis by inhibiting cell proliferation, migration, and invasion, but promoting cell apoptosis. These findings provide molecular insights into the mechanism of HCC and indicate that circ_GLIS2 could serve as a diagnosis marker or therapeutic target for HCC.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
To construct a machine learning algorithm model of lymph node metastasis (LNM) in patients with poorly differentiated-type intramucosal gastric cancer. 1169 patients with postoperative gastric cancer ...were divided into a training group and a test group at a ratio of 7:3. The model for lymph node metastasis was established with python machine learning. The Gbdt algorithm in the machine learning results finds that number of resected nodes, lymphovascular invasion and tumor size are the primary 3 factors that account for the weight of LNM. Effect of the LNM model of PDC gastric cancer patients in the training group: Among the 7 algorithm models, the highest accuracy rate was that of GBDT (0.955); The AUC values for the 7 algorithms were, from high to low, XGB (0.881), RF (0.802), GBDT (0.798), LR (0.778), XGB + LR (0.739), RF + LR (0.691) and GBDT + LR (0.626). Results of the LNM model of PDC gastric cancer patients in test group : Among the 7 algorithmic models, XGB had the highest accuracy rate (0.952); Among the 7 algorithms, the AUC values, from high to low, were GBDT (0.788), RF (0.765), XGB (0.762), LR (0.750), RF + LR (0.678), GBDT + LR (0.650) and XGB + LR (0.619). Single machine learning algorithm can predict LNM in poorly differentiated-type intramucosal gastric cancer, but fusion algorithm can not improve the effect of machine learning in predicting LNM.
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In order to investigate the high loading rate effect on the behaviour and mechanical properties of coal-rock combined body, the dynamic compressive tests were conducted by using the Split-Hopkinson ...Pressure Bar (SHPB) device under the loading rate range from 2.7×105 MPa/s to 4.0×105 MPa/s. The stress-strain curves, dynamic peak stress and strain, elastic modulus, and energy distribution law of coal-rock combined body under different loading rates were analyzed and discussed. The results show that the dynamic stress-strain curves of coal-rock combined body have a double-peak feature under high loading rate range, which can be divided into the initial bearing stage, the bearing decline stage, the bearing enhance stage, and the unstable stage. The first peak stress of the coal-rock combined body is independent of the loading rate, while the dynamic compressive strength (the second peak stress) and dynamic peak strain (the second peak strain) have a strong loading rate effect and will generally increase linearly with the loading rate. The first and second elastic moduli of coal-rock combined body are not sensitive to the loading rate. With the increase of the loading rate, the incident energy and reflective energy of coal-rock combined body increase rapidly, while the change of transmitted energy is very small. The absorption energy ratio of the coal-rock combined body shows a good linear law with the incident energy under different loading rates.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The number of topological defects in the shear flow of active nematic fluids is numerically investigated in this study. The evolution of the flow state of extensile active nematic fluids is explored ...by increasing the activity of active nematic fluids. Evidently, medium-activity active nematic fluids exhibit a highly ordered vortex lattice fluid state. However, high-activity active nematic fluids exhibit a meso-scale turbulent flow accompanied by topological defects. The number of topological defects (
N
def
) increases with increasing shear Reynolds number (
R
e
s
). Fluid viscosity strongly influences
N
def
, while the influence of fluid density is relatively weak.
N
def
decreases with increasing activity length scale (
l
ζ
) value. A small
Re
s
value strongly influences
N
def
, whereas a large
l
ζ
value only weakly influences
N
def
. As the activity increases,
N
def
in contractile active nematic fluids becomes larger than that of extensile active nematic fluids.
Graphical abstract
Graphical abstract represents the flow state of meso-scale turbulent accompanied by topological defects. For the two dimensional case, two types of topological defects, namely comet-like + 1/2 and trefoil-like − 1/2 topological defects
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Photodynamic therapy (PDT) shows a promising synergy with chemotherapy in the therapeutic outcome of malignant cancers. The minimal invasiveness and nonsystemic toxicity are appealing advantages of ...PDT, but combination with chemotherapy brings in the nonselective toxicity. We designed a polymeric nanoparticle system that contains both a chemotherapeutic agent and a photosensitizer to seek improvement for chemo-photodynamic therapy. First, to address the challenge of efficient co-delivery, polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by a π–π stacking interaction, with high loading (41.9 wt %) and the optimal nanoparticle size (50 nm). Second, light given in PDT treatment not only excites Ce6 to produce cytotoxic reactive oxygen species (ROS) but also spatiotemporally activates a cascade reaction to release the loaded drugs. Finally, we report a self-destructive polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone to facilitate drug release upon ROS stimulus. This is achieved by grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate. When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target delivery toxicity is mostly avoided. An oral squamous cell carcinoma that is clinically relevant to PDT was used as the cancer model. We put forward a polymeric system with improved efficiency for chemo-photodynamic therapy and reduced off-target toxicity.
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IJS, KILJ, NUK, PNG, UL, UM
Five metabolites including two new ones, prochaetoviridin A (
) and chaetoindolin A (
), were isolated from the endophytic fungus
CDW7. Compounds
and
were characterized as an isocoumarin and an ...indole alkaloid derivative, respectively, with their structures elucidated by comprehensive spectroscopic analyses including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), NMR, and circular dichroism (CD) comparison. Compounds
⁻
were identified as chaetoviridin A, chaetoglobosin R, and chaetoglobosin T, respectively. Chaetoviridin A (
) exhibited antifungal activity against
with an EC
value of 1.97 μg/mL. In vivo test showed that
displayed a protective efficacy of 64.3% against rape
rot at the dosage of 200 μg/mL, comparable to that of carbendazim (69.2%).
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