This study concerns the turbulent flow field influenced by the scour development around a bridge pier. The scour hole evolution as well as the temporal variation of scour depth around the pier were ...firstly analyzed. Subsequently, the flow fields in front of the pier at different instants during the scour process were measured using particle image velocimetry (PIV). It shows that the scour depth at the pier front exceeds that of the pier side at the later scouring stage. The temporal development of scour depth can be well predicted by a simple practical engineering model based on an exponential function with a change in the two adjustable coefficients. The flow field indicates that with the development of scour hole, the downward flow in front of the pier becomes more prominent, meanwhile the flow becomes more turbulent. The variation tendency for both velocities and turbulence intensities along the streamwise direction in front the pier shows similarity. The Reynolds shear stress generally increases with developing scour hole, and the region with large value enlarges and moves upstream of the scour hole.
Offshore structures are prone to produce a dynamic response under the effect of large wave load. In this paper, the smoothed particle hydrodynamics coupled with finite element (SPH-FE) method is used ...to investigate the dynamic characteristics of structure induced by the water waves. The dam break model is assumed to generate water wave. Firstly, the parameter of particle spacing included in the SPH method is examined and the appropriate value is proposed. Subsequently, the present numerical model is validated by comparing with the available results from the literature. Furthermore, the influence of several parameters on the wave load of the structure and the induced dynamic characteristics is studied, including the water column height, the distance between the water column and structure, and the structure stiffness. The results show that the amplification of the wave load on the bottom of structure is greater than that on the upper part of the structure. The increase of structure stiffness results in a decrease in the displacement at the top of structure, but an increase in the hydrodynamic force at the bottom of structure.
Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles. Substantial evidence for AD pathogenesis suggests that β-site APP cleaving enzyme 1 (BACE1) and γ-secretase ...enzyme initiate the amyloidogenic pathway and produces toxic Aβ peptides that prone to aggregate in the brain. Therefore, the inhibition of BACE1 expression and function is an attractive strategy for AD therapy. In the present work, we made the first finding that activating δ-opioid receptors (DOR) with a specific DOR agonist significantly attenuated BACE1 expression and activity in the highly differentiated PC12 cells with mimicked AD injury, while the application of DOR inhibitor naltrindole reversed the UFP-512 effects, and even caused a major increase in BACE1 expression and activity as well as Aβ42 production in physiological conditions. Knocking-down DOR also enhanced BACE1 protein expression and its activity for APP processing, associating with a significant increase in Aβ42 production. In sharp contrast, activation of μ-opioid receptor (MOR) with DAMGO greatly promoted BACE1 expression and activity with an acceleration of APP cleavage, thus contributing to increased Aβ42 production. DADLE, a less selective DOR agonist that may bind to MOR, had no stable inhibitory effect on BACE1. Similar results were also found in APP mutant (APPswe) SH-SY5Y cell line, providing further validation of the DOR action on BACE1 regulation. Our novel data demonstrated entirely different roles of DOR and MOR in the regulation of BACE1 expression and activity with DOR being neuroprotective against AD injury. These findings provided a novel clue for new strategies of AD therapy via targeting endogenous opioid receptors.
Polymyxin B (PMB) and polymyxin E (colistin, CST) are polymyxin antibiotics, which are considered last-line therapeutic options against multidrug-resistant Gram-negative bacteria in serious ...infections. However, there is increasing risk of resistance to antimicrobial drugs. Effective efflux pump inhibitors (EPIs) should be developed to help combat efflux pump-mediated antibiotic resistance.
sp. PL22-22A was isolated from aquaculture sewage under selection with 8 mg/L PMB, and then its genome was sequenced using Oxford Nanopore and BGISEQ-500 platforms.
(Chryseobacterium Polymyxins Resistance) genes encoding a major facilitator superfamily-type tripartite efflux system, were found in the genome. These genes, and the gene encoding a truncation mutant of CprB from which sequence called CprBc was deleted, were amplified and expressed/co-expressed in
DH5α. Minimum inhibitory concentrations (MICs) of polymyxins toward the various
heterologous expression strains were tested in the presence of 2-128 mg/L PMB or CST. The pumping activity of CprABC was assessed via structural modeling using Discovery Studio 2.0 software. Moreover, the influence on MICs of baicalin, a novel MFS EPI, was determined, and the effect was analyzed based on homology modeling.
Multidrug-resistant bacterial strain
sp. PL22-22A was isolated in this work; it has notable resistance to polymyxin, with MICs for PMB and CST of 96 and 128 mg/L, respectively. A novel MFS-type tripartite efflux system, named CprABC, was identified in the genome of
sp. PL22-22A. Heterologous expression and EPI assays indicated that the CprABC system is responsible for the polymyxin resistance of
sp. PL22-22A. Structural modeling suggested that this efflux system provides a continuous conduit that runs from the CprB funnel through the CprC porin domain to pump polymyxins out of the cell. A specific
-terminal α-helix, CprBc, has an activation function on polymyxin excretion by CprB. The flavonoid compound baicalin was found to affect the allostery of CprB and/or obstruct the substrate conduit, and thus to inhibit extracellular polymyxin transport by CprABC.
Novel MFS-type tripartite efflux system CprABC in
sp. PL22-22A mediates resistance to polymyxins, and baicalin is a promising EPI.
To explore the clinical value of contrast-enhanced ultrasound (CEUS) quantitative analysis in the evaluation and prognosis of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC).
...Eighty-three consecutive patients undergoing neoadjuvant chemoradiotherapy and total mesorectal excision for LARC were retrospectively included. According to pathological results, patients were categorized into complete or incomplete response groups. Differences in ultrasonic parameters, pathological results, and clinical data between groups were evaluated. The cutoff point for a complete response as determined by quantitative analysis of CEUS was assessed using a receiver operating characteristic curve; additionally, overall survival (OS) and progression-free survival (PFS) were analyzed.
Of the 83 patients, 12 (14.5%) achieved a complete response and 71 (85.5%) did not. There were significant between-group differences in carcinoembryonic antigen (CEA) levels, differentiation degree, proportion of tumor occupying the lumen, anterior-posterior and superior-inferior diameters of the lesion, and intensity of enhancement (P<0.05). CEUS quantitative analysis showed significant between-group differences in peak intensity (PI) and area under the curve (AUC) values (P<0.05). The OS and PFS of patients with high PI, high AUC value, and poorly differentiated cancer were significantly worse than those with low PI, low AUC values, and moderately to highly differentiated cancer (P<0.05). High CEA levels (hazard ratio: 1.02, 95% confidence interval: 1.01-1.04; P=0.002) and low differentiation (2.72, 1.12-6.62; P=0.028) were independent risk factors for PFS and OS.
CEUS can predict the response to neoadjuvant treatment in patients with LARC. CEUS quantitative analysis is helpful for clinical prognosis.
This study concerns the evolution of flow field and hydrodynamic characteristics within the developing scour hole around a four-pile group with 2 × 2 arrangement. The instantaneous velocities in ...scour holes at four typical stages during the scouring process were measured by an acoustic Doppler velocimeter (ADV). The evolution and spatial distribution of the time-averaged flow field, turbulence, and the corresponding hydrodynamic characteristics within scour holes were compared. The time-averaged flow field shows that the reverse flow, downward flow, and horseshoe vortex are formed in the upstream of the pile group. During the scouring process, the mean components of flow characteristics (i.e., mean velocity, vorticity, and bed shear stress) around the pile group decrease while the fluctuating components (i.e., turbulence intensity) intensify simultaneously. Similarity of turbulence intensity profiles was found within different scour holes. The horseshoe vortex at upstream of each pile merges and the shear layer in the gap region extends when the dimension of the scour hole increases to that of equilibrium scour status, indicating that the four piles behave more like a single bluff body. With the development of scour holes, the large-scale horseshoe vortex system becomes more stable and the dissipation of small-scale eddies becomes more significant.
Circulating microRNAs (miRNAs) are emerging as promising biomarkers for human cancer. In the current study, we investigated the potential use of serum miRNAs as biomarkers for diagnosis and prognosis ...in a cohort of Chinese astrocytoma patients.
An initial screening of the circulating miRNA expression profile was performed on pooled serum samples from 10 preoperative patients and 10 healthy controls using a TaqMan low-density array. The selected serum miRNAs were then validated in 90 preoperative patients and 110 healthy controls who were randomly divided into a training set and a validation set. An additional double-blind test was performed in 50 astrocytomas and 50 controls to assess the serum miRNA-based biomarker accuracy in predicting astrocytoma. The differentially expressed miRNAs were evaluated in paired preoperative and postoperative serum samples from 73 astrocytoma patients. The correlation of the miRNA levels with survival in astrocytoma samples was estimated.
Nine serum miRNAs were significantly increased in the astrocytoma patients. The biomarker composed of these 9 miRNAs had high sensitivity, specificity, and accuracy. These 9 miRNAs were markedly decreased in the serum after operation. The upregulation of miR-20a-5p, miR-106a-5p, and miR-181b-5p was associated with advanced clinical stages of astrocytoma. Kaplan-Meier survival analysis showed that the high expression of miR-19a-3p, miR-106a-5p, and miR-181b-5p was significantly associated with poor patient survival. Finally, the combined 3-miRNAs panel was an important prognostic predictor, independent of other clinicopathological factors.
The results indicated the potential of serum miRNAs as novel diagnostic and prognostic biomarkers for human astrocytoma.
Abstract CD8 + T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. ...However, whether the changes in CD8 + T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8 + T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8 + T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8 + T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8 + T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8 + T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8 + T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.
Unrest began in July 2021 at Askja volcano in the Northern Volcanic Zone (NVZ) of Iceland. Its most recent eruption, in 1961, was predominantly effusive and produced ∼0.1 km3 lava field. The last ...plinian eruption at Askja occurred in 1875. Geodetic measurements between 1983 and 2021 detail subsidence of Askja, decaying in an exponential manner. At the end of July 2021, inflation was detected at Askja volcano, from GNSS observations and Sentinel‐1 interferograms. The inflationary episode can be divided into two periods from the onset of inflation until September 2023. An initial period until 20 September 2021 when geodetic models suggest transfer of magma (or magmatic fluids) from within the shallowest part of the magmatic system (comprising an inflating and deflating source), potentially involving silicic magma. A following period when one source of pressure increase at shallow depth can explain the observations.
Plain Language Summary
Askja volcano, situated in the Northern Volcanic Zone in Iceland, has been quiet since its last eruption in 1961, with surface deformation measurements from 1983 to 2021 displaying a decaying subsidence signal within the Askja caldera. However, at the end of July 2021, the volcano began to inflate. This was detected on both GNSS and satellite observations. As of September 2023, ∼65 cm of uplift had been measured at GNSS station OLAC. Modeling of surface deformation measurements indicates that the inflation was triggered by upward migration of melt (or magmatic fluids).
Key Points
At the end of July 2021, Askja volcano began to inflate—detected on both GNSS and satellite observations, ending 1983–2021 subsidence
Geodetic modeling indicates upward migration of magma, feeding a magma body at an inferred depth of 2.5–3.1 km under the main Askja caldera
Start of unrest was associated with magma transfer within the upper part of the system, followed by possible additional influx from depth
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