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The fluid‐flow properties of fractures have received increasing attention regarding the role of geofluids in the genesis of slow and fast earthquakes and recent advances in geoengineering developments. Geophysical observations are promising tools to remotely estimate crustal permeability changes; however, quantitative interpretations are limited by the rock‐physical models' paucity for fractures. This study investigated changes in permeability, resistivity, and their respective relationships at elevated stress by performing numerical simulations of different fracture models with varying fracture size, roughness, and shear displacement. Numerical results and microscopic flow analysis demonstrate that permeability–resistivity relationships are controlled by percolation and are less dependent on fracture geometric characteristics. Our finding suggests that the permeability evolution of fractures can be formulated with resistivity changes independent of both fracture size and microstructure, the trends of which can be predicted using Archie's exponent. The extension to the electro‐mechanical relationship further derives the potential applications of estimating stress changes. Plain Language Summary Monitoring the flow of fluids through underground fractures is important for developing earth resources and understanding the generation of both slow and fast earthquakes. This can be realized by observing physical properties underground such as electrical resistivity; however, the relationships between electrical and hydraulic properties are poorly understood because we have limited data on rock fractures. Thus, in this study, we explored changes in the hydraulic and electrical properties of synthetic rock fractures by subjecting them to increasing normal stress and shear displacement while varying the properties of the fracture surface topographies and length scales referring to natural data. We formulated the relationship between electrical resistivity and permeability invariant of fracture size, roughness, shear displacement, and normal stress based on both the theoretical model and empirical Archie's equation. We found that the rigorous relationship is controlled by the local connection of the fluid‐flow paths based on the microscopic flow analysis. The proposed formula can estimate the permeability evolution of fractures using resistivity data and is a better approach compared to porosity estimation because resistivity–porosity relationship can change depending on the tortuosity or connectivity. The extension to the electro‐mechanical relationship also derives the potential applications of estimating changes in pore pressure. Key Points Numerical results clarify the dependencies of fracture size, roughness, shear displacement, and stress on permeability and resistivity Flow path percolation can be correlated with tortuosity, which controls the rigorous resistivity–porosity and –permeability relationships Archie's exponent is constant for a percolated single fracture and can be used for monitoring permeability and pore pressure change

We measured the residual stress tensor in a nitrogen-doped chemical vapor deposition (001) diamond film. The stress tensor was evaluated from the amount of the shift in optically detected magnetic resonance (ODMR) spectra of NV center in the diamond. A confocal microscopy setup was used to observe the spatial variation of the stress tensor in the diamond film. We found that the components of the stress tensor, σ , σ , σ and σ + σ + σ , of the residual stress were approximately 0.077, -0.39, -0.67 and 1.52 GPa, respectively, in the x = [100], y = [010], z = [001] coordinate system. Regarding the components of the shear stress, σ , σ and σ , the nitrogen-doped CVD diamond film grown in this study had mainly sheared stress in the z-direction, which was the growth direction of the CVD diamond film. In addition, regarding axial stress σ + σ + σ , the CVD diamond film was subjected to compressive stress. Due to this compressive stress, the volume of the CVD diamond film decreased by approximately 0.073%. We considered that nitrogen doping contributed to the decrease in volume of the CVD diamond film.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Background:Periprosthetic joint infections (PJIs) with bacterial culture-negative results are challenging to diagnose and manage. Biomarkers such as C-reactive protein and alpha-defensin are often reported to be elevated in patients with inflammatory rheumatic diseases. Therefore, it is difficult to judge whether elevations in biomarkers are caused by infection or flare of a rheumatic disease. To increase the sensitivity of detecting causative microorganisms, a number of methods, including polymerase chain reaction (PCR), have been reported. PCR-lateral flow can detect methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), and methicillin-resistant coagulase-negative Staphylococcus (MR-CNS). In the clinical setting, we routinely use PCR-lateral flow for the diagnosis of PJI in patients with rheumatoid arthritis at risk for culture-negative infections, such as patients with prior antimicrobial therapy or patients with documented negative results from prior or present bacterial cultures.Objectives:To clarify the clinical usefulness of PCR-lateral flow for the diagnosis and management of PJI in patients with rheumatoid arthritis at risk for culture-negative infections.Methods:This retrospective study included suspected cases of PJI between 2018 and 2023 at our institution. Diagnosis of PJI was determined based on the entire clinical course by two rheumasurgeons. Using genomic DNA isolated from synovial fluid or soft tissues, multiplex PCR was performed with two genetic markers: the S. aureus-specific gene femA and the antibiotic resistant gene mecA. PCR products were qualitatively assessed using the lateral flow method. PCR-lateral flow results, demographics, laboratory and culture findings, and clinically diagnosis of PJI were investigated.Results:This analysis included 18 episodes in 16 patients (13 females and 3 males; average age, 77 years). There were 5 (28%) bacterial culture-positive episodes and 13 (78%) culture-negative episodes. PJI was clinically diagnosed in 13 episodes. The sensitivity of bacterial culture and PCR-lateral flow was 38% and 38%, respectively. Five episodes without infection had both negative bacterial culture and PCR-lateral flow results; the final diagnoses were flare of rheumatoid arthritis (n = 3), pseudogout attack (n = 1), and aseptic loosening (n = 1). Among 8 PJI episodes with bacterial culture-negative results, 4 episodes were identified as MR-CNS (n = 3) or MSSA (n = 1) based on PCR-lateral flow. PCR-lateral flow results were consistent with the clinical course and antimicrobial responsiveness.Conclusion:The PCR- lateral flow method can identify false-negative bacterial cultures and provide useful information for the diagnosis and management of PJI in patients with rheumatoid arthritis at risk for bacterial culture-negative infections.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

The causes for forearc basin and megathrust rupture zone segmentation are controversial. The Nankai forearc, Japan, is separated into five domains based on topography: Enshu, Kumano, Muroto, Tosa, and Hyuga. The boundaries of these domains correspond to the rupture limits of large earthquakes. We examined the geologic structure of the boundary region between the Kumano and Muroto domains off the Kii Peninsula using multichannel seismic reflection data to evaluate the role of upper plate composition in controlling segmentation. The results suggest that thick cover sediments and underlying accretionary prism are obliquely thrust landward over the igneous basement complex rock in the region of offshore of Cape Shionomisaki and separate the forearc basin. The igneous basement complex rocks directly overlying the plate interface in the hypocentral regions of 1944 Tonankai and 1946 Nankai earthquakes. The 1944 earthquake originated at the base of the complex, and the rupture extent slipped past its basement boundary, whereas the 1946 event nucleated at the updip boundary of the basement complex. The dense igneous rocks might have worked as a heavily loaded barrier on the seismogenic megathrust and separated the rupture area of both the earthquakes. Upper plate geology may be an important factor in controlling seismogenesis in the Nankai Trough and may serve as an example for understanding the controls on megathrust slip in other subduction zones. Plain Language Summary The Nankai Trough, Japan is the place where quakes nucleate in the margin and tsunamis repeatedly devastated circum‐Pacific societies. When, where, why, and how the quakes were started in the trench is a central scientific question but unsolved. The historical records of earthquakes suggest that the rupture started around Cape Shionomisaki of the Kii Peninsula, where there is also a topographic segment boundary of the ∼2,000 m deep basin in the middle continental slope. Our research of the geologic structure beneath the earthquake epicenters indicates a dense and hard rock mass situated upon the hypocenters of 1944, and 1946 megaquakes off Cape Shionomisaki. The rock mass might have worked as a heavy load and barrier on the low angle dipping plate boundary fault when the fault slipped the large rupture was propagated in the Nankai Trough. Key Points The Nankai forearc basin is separated off the Kii Peninsula owing to the existence of middle Miocene igneous basement in the upper plate The rupture areas of the 1944 Tonankai, 1946 Nankai, and 2016 off‐Mie earthquakes appear to be controlled by the igneous basement The shallow distribution of very low‐frequency earthquakes and tremors are related to the geological heterogeneity of the upper plate

Antimicrobial resistance has emerged as one of the leading public health threats of the twenty-first century. Gram-negative pathogens have been a major contributor to the declining efficacy of antibiotics through both acquired resistance and tolerance. In this study, a pan-drug resistant (PDR), NDM-1 and CTX-M-15 co-producing isolate of K. pneumoniae, CDC Nevada, ( Kp Nevada) was exposed to the clinical combination of aztreonam + ceftazidime/avibactam (ATM/CAZ/AVI) to overcome metallo-β-lactamases. Unexpectedly, the β-lactam combination resulted in long filamentous cell formation induced by PBP3 inhibition over 168 h in the hollow fiber infection model experiments with eventual reversion of the total population upon drug removal. However, the addition of imipenem to the two drug β-lactam combination was highly synergistic with suppression of all drug resistant subpopulations over 5 days. Scanning electron microscopy and fluorescence microscopy for all imipenem combinations in time kill studies suggested a role for imipenem in suppression of long filamentous persisters, via the formation of metabolically active spheroplasts. To complement the imaging studies, salient transcriptomic changes were quantified using RT-PCR and novel cassette assay evaluated β-lactam permeability. This showed significant upregulation of both spheroplast protein Y (SPY), a periplasmic chaperone protein that has been shown to be related to spheroplast formation, and penicillin binding proteins (PBP1, PBP2, PBP3) for all combinations involving imipenem. However, with aztreonam alone, pbp1, pbp3 and spy remained unchanged while pbp2 levels were downregulated by > 25%. Imipenem displayed 207-fold higher permeability as compared with aztreonam (mean permeability coefficient of 17,200 nm/s). Although the clinical combination of aztreonam/avibactam and ceftazidime has been proposed as an important treatment of MBL Gram-negatives, we report the first occurrence of long filamentous persister formation. To our knowledge, this is the first study that defines novel β-lactam combinations involving imipenem via maximal suppression of filamentous persisters to combat PDR CDC Nevada K. pneumoniae .

Monitoring the hydraulic properties within subsurface fractures is vitally important in the contexts of geoengineering developments and seismicity. Geophysical observations are promising tools for remote determination of subsurface hydraulic properties; however, quantitative interpretations are hampered by the paucity of relevant geophysical data for fractured rock masses. This study explores simultaneous changes in hydraulic and geophysical properties of natural rock fractures with increasing normal stress and correlates these property changes through coupling experiments and digital fracture simulations. Our lattice Boltzmann simulation reveals transitions in three-dimensional flow paths, and finite-element modeling enables us to investigate the corresponding evolution of geophysical properties. We show that electrical resistivity is linked with permeability and flow area regardless of fracture roughness, whereas elastic wave velocity is roughness-dependent. This discrepancy arises from the different sensitivities of these quantities to microstructure: velocity is sensitive to the spatial distribution of asperity contacts, whereas permeability and resistivity are insensitive to contact distribution, but instead are controlled by fluid connectivity. We also are able to categorize fracture flow patterns as aperture-dependent, aperture-independent, or disconnected flows, with transitions at specific stress levels. Elastic wave velocity offers potential for detecting the transition between aperture-dependent flow and aperture-independent flow, and resistivity is sensitive to the state of connection of the fracture flow. The hydraulic-electrical-elastic relationships reported here may be beneficial for improving geophysical interpretations and may find applications in studies of seismogenic zones and geothermal reservoirs.

Background: Glioma stem-like cell (GSC) properties are responsible for gliomagenesis and recurrence. GSCs are invasive but its mechanism remains to be elucidated. Here, we attempted to identify the molecules that promote invasion in GSCs. Methods: Neurospheres and CD133 + cells were collected from glioblastoma (GBM) specimens and glioma cell lines by sphere-formation method and magnetic affinity cell sorting, respectively. Differential expression of gene candidates, its role in invasion and its signaling pathway were evaluated in glioma cell lines. Results: Neurospheres from surgical specimens attached to fibronectin and laminin, the receptors of which belong to the integrin family. Integrin α 3 was overexpressed in CD133 + cells compared with CD133 − cells in all the glioma cell lines (4 out of 4). Immunohistochemistry demonstrated the localisation of integrin α 3 in GBM cells, including invading cells, and in the tumour cells around the vessels, which is believed to be a stem cell niche. The expression of integrin α 3 was correlated with migration and invasion. The invasion activity of glioma cells was linked to the phosphorylation of extracellular signal–regulated kinase (ERK) 1/2. Conclusion: Our results suggest that integrin α 3 contributes to the invasive nature of GSCs via ERK1/2, which renders integrin α 3 a prime candidate for anti-invasion therapy for GBM.

Background Understanding the mechanism of antimicrobial action is critical for improving antibiotic therapy. For the first time, we integrated correlative metabolomics and transcriptomics of Pseudomonas aeruginosa to elucidate the mechanism of synergistic killing of polymyxin–rifampicin combination. Methods Liquid chromatography-mass spectrometry and RNA-seq analyses were conducted to identify the significant changes in the metabolome and transcriptome of P. aeruginosa PAO1 after exposure to polymyxin B (1 mg/L) and rifampicin (2 mg/L) alone, or in combination over 24 h. A genome-scale metabolic network was employed for integrative analysis. Results In the first 4-h treatment, polymyxin B monotherapy induced significant lipid perturbations, predominantly to fatty acids and glycerophospholipids, indicating a substantial disorganization of the bacterial outer membrane. Expression of ParRS, a two-component regulatory system involved in polymyxin resistance, was increased by polymyxin B alone. Rifampicin alone caused marginal metabolic perturbations but significantly affected gene expression at 24 h. The combination decreased the gene expression of quorum sensing regulated virulence factors at 1 h (e.g. key genes involved in phenazine biosynthesis, secretion system and biofilm formation); and increased the expression of peptidoglycan biosynthesis genes at 4 h. Notably, the combination caused substantial accumulation of nucleotides and amino acids that last at least 4 h, indicating that bacterial cells were in a state of metabolic arrest. Conclusion This study underscores the substantial potential of integrative systems pharmacology to determine mechanisms of synergistic bacterial killing by antibiotic combinations, which will help optimize their use in patients. Graphical Abstract

Yellowtails Seriola quinqueradiata are an important fishery resource around Japan. Here we investigated the movement ecology and habitat utilization of this migratory fish. Archival tags were implanted in 26 adult yellowtails (61−90 cm in fork length) to examine their seasonal movement patterns and vertical distribution. Yellowtails were captured and released around Noto Peninsula in the Japan Sea on 27 May 2004. Eight individuals were recaptured more than 2 mo later, and we analyzed their daily position and vertical movement with ambient water temperature recorded in 60 or 120 s intervals. Most yellowtail individuals moved from the central coast of Japan to the north (from the west of Tsugaru Strait to the west of Hokkaido) in June. Individuals resided in the northern part of the Japan Sea from summer to mid-fall (late July to late October). Seasonal thermoclines developed during this northward movement and subsequent period of residency, with individuals primarily occupying the surface mixed layer during the daytime and at night; however, individuals made frequent short dives through the thermocline, especially during the daytime. These phenomena may be related to foraging based on the distribution of their prey. In late October, yellowtails started a rapid southward movement, primarily remaining in vertical thermal mixing coastal areas, and not entering the coldwater masses that formed offshore. This southward movement pattern might indicate that yellowtails avoid cold offshore water temperatures.