Abstract Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, ...the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.
Occult peritoneal metastasis (PM) in advanced gastric cancer (AGC) patients is highly possible to be missed on computed tomography (CT) images. Patients with occult PMs are subject to late detection ...or even improper surgical treatment. We therefore aimed to develop a radiomic nomogram to preoperatively identify occult PMs in AGC patients.
A total of 554 AGC patients from 4 centers were divided into 1 training, 1 internal validation, and 2 external validation cohorts. All patients’ PM status was firstly diagnosed as negative by CT, but later confirmed by laparoscopy (PM-positive n = 122, PM-negative n = 432). Radiomic signatures reflecting phenotypes of the primary tumor (RS1) and peritoneum region (RS2) were built as predictors of PM from 266 quantitative image features. Individualized nomograms of PM status incorporating RS1, RS2, or clinical factors were developed and evaluated regarding prediction ability.
RS1, RS2, and Lauren type were significant predictors of occult PM (all P < 0.05). A nomogram of these three factors demonstrated better diagnostic accuracy than the model with RS1, RS2, or clinical factors alone (all net reclassification improvement P < 0.05). The area under curve yielded was 0.958 95% confidence interval (CI) 0.923–0.993, 0.941 (95% CI 0.904–0.977), 0.928 (95% CI 0.886–0.971), and 0.920 (95% CI 0.862–0.978) for the training, internal, and two external validation cohorts, respectively. Stratification analysis showed that this nomogram had potential generalization ability.
CT phenotypes of both primary tumor and nearby peritoneum are significantly associated with occult PM status. A nomogram of these CT phenotypes and Lauren type has an excellent prediction ability of occult PM, and may have significant clinical implications on early detection of occult PM for AGC.
Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since ...they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein–ligand binding, protein–protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields.
Abstract
Understanding the sources of lunar water is crucial for studying the history of lunar evolution, as well as the interaction of solar wind with the Moon and other airless bodies. Recent ...orbital spectral observations revealed that the solar wind is a significant exogenous driver of lunar surficial hydration. However, the solar wind is shielded over a period of 3–5 days per month as the Moon passes through the Earth’s magnetosphere, during which a significant loss of hydration is expected. Here we report the temporal and spatial distribution of polar surficial OH/H
2
O abundance, using Chandrayaan-1 Moon Mineralogy Mapper (
M
3
) data, which covers the regions inside/outside the Earth’s magnetosphere. The data shows that polar surficial OH/H
2
O abundance increases with latitude, and that the probability of polar surficial OH/H
2
O abundance remains at the same level when in the solar wind and in the magnetosphere by controlling latitude, composition, and lunar local time. This indicates that the OH/H
2
O abundance in the polar regions may be saturated, or supplemented from other possible sources, such as Earth wind (particles from the magnetosphere, distinct from the solar wind), which may compensate for thermal diffusion losses while the Moon lies within the Earth’s magnetosphere. This work provides some clues for studies of planet–moon systems, whereby the planetary wind serves as a bridge connecting the planet with its moons.
Ultrathin FeO(1
1
1) films grown on Pt(1
1
1) unexpectedly showed high activity towards CO oxidation. The reaction proceeds through the formation of a well-ordered, oxygen-rich FeO
x
(1
<
x
<
2) ...film. In CO-rich ambient the film dewets the Pt surface, ultimately resulting in highly dispersed iron oxide particles on Pt(1
1
1).
CO oxidation on a clean Pt(1
1
1) single crystal and thin iron oxide films grown on Pt(1
1
1) was studied at different CO:O
2 ratios (between 1:5 and 5:1) and partial pressures up to 60
mbar at 400–450
K. Structural characterization of the model catalysts was performed by scanning tunnelling microscopy, low energy electron diffraction, Auger electron spectroscopy and temperature-programmed desorption. It was found that monolayer FeO(1
1
1) films grown on Pt(1
1
1) were much more active than clean Pt(1
1
1) and nm-thick Fe
3O
4(1
1
1) films at all reaction conditions studied. Post-characterization of the catalysts revealed that at CO:O
2
>
1 the FeO(1
1
1) film dewets the Pt surface with time, ultimately resulting in highly dispersed iron oxide particles on Pt(1
1
1). The film dewetting was monitored
in situ by polarization-modulated infrared reflection absorption spectroscopy. The reaction rate at 450
K exhibited first order for O
2 and non-monotonously depended on CO pressure. In O
2-rich ambient the films were enriched with oxygen while maintaining the long-range ordering. Based on the structure-reactivity relationships observed for the FeO/Pt films, we propose that the reaction proceeds through the formation of a well-ordered, oxygen-rich FeO
x
(1
<
x
<
2) film that reacts with CO through the redox mechanism. The reaction-induced dewetting in fact deactivates the catalyst. The results may aid in our deeper understanding of reactivity of metal particles encapsulated by thin oxide films as a result of strong metal–support interaction.
Dapsone is an important medication for the treatment of leprosy, but a life-threatening drug hypersensitivity syndrome develops in some patients. In this report from China, an
HLA-B
locus is ...identified as a strong genetic risk factor for the syndrome.
Dapsone (4-4′-sulfonyldianiline), which was first synthesized in 1908,
1
is both an antibiotic and an antiinflammatory agent. Dapsone alone or in combination with other drugs has been used for the prevention and treatment of infectious diseases (e.g., leprosy, malaria, and actinomycetoma, as well as
Pneumocystis jirovecii
pneumonia in persons with human immunodeficiency virus HIV infection) and chronic inflammatory diseases characterized by the infiltration of neutrophils or eosinophils (e.g., dermatitis herpetiformis, linear IgA dermatosis, subcorneal pustular dermatosis, and erythema elevatum diutinum).
2
,
3
About 0.5 to 3.6% of persons treated with dapsone have a drug hypersensitivity syndrome,
3
–
5
which was first described by . . .
We previously demonstrated that fermitin family member 1 (FERMT1) was significantly overexpressed in colon cancer (CC) and associated with poor metastasis-free survival. This study aimed to ...investigate the precise role of FERMT1 in CC metastasis and the mechanism by which FERMT1 is involved in the epithelial-mesenchymal transition (EMT). Correlations between FERMT1 and EMT markers (E-cadherin, Slug, N-cadherin and β-catenin) were examined via immunohistochemistry in a cohort of CC tissues and adjacent normal colon mucosae. A series of in vitro and in vivo assays were performed to elucidate the function of FERMT1 in CC metastasis and underlying mechanisms. The upregulated expression of FERMT1 in CC tissues correlated positively with that of Slug, N-cadherin and β-catenin, but correlated inversely with E-cadherin expression. Altered FERMT1 expression led to marked changes in the proliferation, migration, invasion and EMT markers of CC cells both in vitro and in vivo. Investigations of underlying mechanisms found that FERMT1 interacted directly with β-catenin and activated the Wnt/β-catenin signaling pathway by decreasing the phosphorylation level of β-catenin, enhancing β-catenin nuclear translocation and increasing the transcriptional activity of β-catenin/TCF/LEF. Activation of the Wnt/β-catenin pathway by CHIR99021 reversed the effect of FERMT1 knockdown, whereas inhibition of the Wnt/β-catenin pathway by XAV939 impaired the effect of FERMT1 overexpression on EMT and cell motility. In conclusion, findings of this study suggest that FERMT1 activates the β-catenin transcriptional activity to promote EMT in CC metastasis.
The micromechanical behavior of high-strength steels with multiple phases was characterized using the in situ high-energy X-ray diffraction technique. For the materials investigated, the {2
0
0} ...lattice strains of the constituent phases (ferrite, bainite and martensite) with similar crystal structures were determined by separating their overlapped diffraction peaks and then examining the respective changes in peak positions during deformation. Based on those experimental data, the anisotropic elastic and plastic properties of the steels were simulated using a self-consistent model for predicting the grain-to-grain and phase-to-phase interactions. The constitutive laws for describing the elastic and plastic behavior of each constituent phase were directly obtained by comparing the predicted lattice strain distributions with the measured ones. The transmission electron microscopy observations of the microstructure development verified the partitioning of plastic strains among different phases. The present investigations provide a fundamental understanding of the stress partitioning of soft and hard phases, and the different work-hardening rates of the multiphase steels.
Purpose
To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial ...chemoembolization (cTACE) treatments.
Methods
367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1–2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments.
Results
There was no difference in complete response (CR) (
P
= 0.671) and objective response rate (ORR) (
P
= 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups (
P
= 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1–3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1–3 month post-DEB-TACE (
P
= 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups (
P
= 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups.
Conclusion
DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments.
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