The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has remained unclear to date. ...Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology, process recruitment to the site of injury, and adaptation to changes in cellular volume in a cell-autonomous manner via regulating membrane conductance. In addition, microglial NKCC1 deficiency results in NLRP3 inflammasome priming and increased production of interleukin-1β (IL-1β), rendering microglia prone to exaggerated inflammatory responses. In line with this, central (intracortical) administration of the NKCC1 blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels. In contrast, systemic bumetanide application decreased inflammation in the brain. Microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema and worse neurological outcome. Thus, NKCC1 emerges as an important player in controlling microglial ion homeostasis and inflammatory responses through which microglia modulate brain injury. The contribution of microglia to central NKCC1 actions is likely to be relevant for common neurological disorders.
This work presents Global Positioning System-Simultaneous Localization and Mapping (GPS-SLAM), an augmented version of Oriented FAST (Features from accelerated segment test) and Rotated BRIEF (Binary ...Robust Independent Elementary Features) feature detector (ORB)-SLAM using GPS and inertial data to make the algorithm capable of dealing with low frame rate datasets. In general, SLAM systems are successful in case of datasets with a high frame rate. This work was motivated by a scarce dataset where ORB-SLAM often loses track because of the lack of continuity. The main work includes the determination of the next frame's pose based on the GPS and inertial data. The results show that this additional information makes the algorithm more robust. As many large, outdoor unmanned aerial vehicle (UAV) flights save the GPS and inertial measurement unit (IMU) data of the capturing of images, this program gives an option to use the SLAM algorithm successfully even if the dataset has a low frame rate.
Mesenchymal stem cells (MSCs) are an integral part of the tumor microenvironment (TME); however, their role is somewhat controversial: conflicting reports suggest that, depending on the stage of ...tumor development, MSCs can either support or suppress tumor growth and spread. Additionally, the influence of MSCs on drug resistance is also ambiguous. Previously, we showed that, despite MSCs proliferating significantly more slowly than cancer cells, there are chemotherapeutic drugs which proved to be similarly toxic to both cell types. Here we established 2D co-cultures and 3D co-culture spheroids from different ratios of GFP-expressing, adipose tissue-derived MSCs and A431 epidermoid carcinoma cells tagged with mCherry to investigate the effect of MSCs on cancer cell growth, survival, and drug sensitivity. We examined the cytokine secretion profile of mono- and co-cultures, explored the inner structure of the spheroids, applied MSC-(nutlin-3) and cancer cell-targeting (cisplatin) treatments separately, monitored the response with live-cell imaging and identified a new, double-fluorescent cell type emerging from these cultures. In 2D co-cultures, no effect on proliferation or drug sensitivity was observed, regardless of the changes in cytokine secretion induced by the co-culture. Conversely, 3D spheroids developed a unique internal structure consisting of MSCs, which significantly improved cancer cell survival and resilience to treatment, suggesting that physical proximity and cell-cell connections are required for MSCs to considerably affect nearby cancer cells. Our results shed light on MSC-cancer cell interactions and could help design new, better treatment options for tumors.
In recent years, several changes have occurred in the management of chronic immunological conditions with the emerging use of targeted therapies. This two-phase cross-sectional study was conducted ...through structured in-person interviews in 2018–2019 and 2022. Additional data sources included ambulatory medical records and the itemized reimbursement reporting interface of the National Health Insurance Fund. Drug interactions were analyzed using the UpToDate Lexicomp, Medscape drug interaction checker, and Drugs.com databases. The chi-square test was used, and odds ratios (ORs) were calculated. In total, 185 patients participated. In 53% of patients (n = 53), a serious drug–drug interaction (DDI) was identified (mean number: 1.07 ± 1.43, 0–7), whereas this value was 38% (n = 38) for potential drug–supplement interactions (mean number: 0.58 ± 0.85, 0–3) and 47% (n = 47) for potential targeted drug interactions (0.72 ± 0.97, 0–5) in 2018. In 2022, 78% of patients (n = 66) were identified as having a serious DDI (mean number: 2.27 ± 2.69, 0–19), 66% (n = 56) had a potential drug–supplement interaction (mean number: 2.33 ± 2.69, 0–13), and 79% (n = 67) had a potential targeted drug interactions (1.35 ± 1.04, 0–5). Older age (>60 years; OR: 2.062), female sex (OR: 3.387), and polypharmacy (OR: 5.276) were identified as the main risk factors. Screening methods and drug interaction databases do not keep pace with the emergence of new therapeutics.
Identity recovery in people diagnosed with schizophrenia who have committed homicide poses several difficulties. Premorbid mental illnesses, the experience of psychosis, and the absence of cohesive ...ego functions may result in the inability to integrate the homicidal act into self-identity. Problems with integration increase the risk of recidivism and further mental problems. The aim of the present research was to explore how homicidal people diagnosed with schizophrenia make sense of their actions, and how they identify with the homicide.
Six semi-structured interviews were conducted at a long-term psychiatric home with people who had committed homicide and who had been diagnosed with schizophrenia. The interviews were transcribed verbatim and analysed using interpretative phenomenological analysis (IPA), an idiographic method rooted in phenomenologist traditions that focuses on how participants experience and make sense of events in their lives, and how those events affect their identity and sense of self.
Three personal experiential themes were established as a result of the analysis: (1) homicide and responsibility; (2) homicide and self; and (3) control over threats to self and self-evaluation. (1) Homicide was often reported to have been committed in a non-conscious, delusional state that may have led to the loss of self-determination. (2) Our interviewees struggled to integrate their acts into their identities. They distanced themselves from the crime or held multiple, parallel interpretations of the act. (3) Recovering patients experienced the constant threat of entering into a delusional reality and losing control. The importance of control was central to their self-evaluation. The patients appeared to distance themselves from the homicidal act and to regard their delusional selves as a threat to their lives.
Therapy aimed at bolstering self-control, supporting the integration of the fragmented self, and raising awareness of the connections between delusional reality and standard, intersubjective reality may be helpful in reducing the instability of the self. Therapy aimed at processing complex grief and loss of family is also needed.
Mesenchymal stem cells (MSCs) or fibroblasts are one of the most abundant cell types in the tumor microenvironment (TME) exerting various anti- and pro-apoptotic effects during tumorigenesis, ...invasion, and drug treatment. Despite the recently discovered importance of MSCs in tumor progression and therapy, the response of these cells to chemotherapeutics compared to cancer cells is rarely investigated. A widely accepted view is that these naive MSCs have higher drug tolerance than cancer cells due to a significantly lower proliferation rate. Here, we examine the differences and similarities in the sensitivity of MSCs and cancer cells to nine diverse chemotherapy agents and show that, although MSCs have a slower cell cycle, these cells are still sensitive to various drugs. Surprisingly, MSCs showed similar sensitivity to a panel of compounds, however, suffered fewer DNA double-stranded breaks, did not enter into a senescent state, and was virtually incapable of apoptosis. Our results suggest that MSCs and cancer cells have different cell fates after drug treatment, and this could influence therapy outcome. These findings could help design drug combinations targeting both MSCs and cancer cells in the TME.
•New formula predicts temperature in ductile shear zones formed by thermal softening.•New localization criterion is based on heat transfer across shear zone.•Thermal thickness of shear zone is ...considerably larger than finite strain thickness.•We numerically model 1D, 2D and 3D shear zones under pure and simple shear.•Thermal softening likely responsible for ductile strain localization in lithosphere.
The generation of ductile shear zones is essential for the formation of tectonic plate boundaries, such as subduction or strike-slip zones. However, the primary mechanism of ductile strain localization is still contentious. We study here the spontaneous generation of ductile shear zones by thermal softening using thermo-mechanical numerical simulations for linear and power-law viscous flow in one-dimension (1D), 2D and 3D. All models are velocity-driven. The 1D model exhibits bulk simple shear whereas the 2D and 3D models exhibit bulk pure shear. The initial conditions include a small temperature perturbation in otherwise homogeneous material. We use a series of 1D simulations to determine a new analytical formula which predicts the temperature evolution inside the shear zone. This temperature prediction requires knowledge of only the boundary velocity, flow law and thermal parameters, but no a priori information about the shear zone itself, such as thickness, stress and strain rate. The prediction is valid for 1D, 2D and 3D shear zones in bulk pure and simple shear. The results show that shear heating dominates over conductive cooling if the relative temperature increase is >50°C. The temperature variation induced by the shear zone is nearly one order of magnitude wider than the corresponding finite strain variation so that no significant temperature variation occurs between shear zone and wall rock. Applying typical flow laws for lithospheric rocks shows that shear zone generation by thermal softening occurs for typical plate tectonic velocities of few cm.yr−1 or strain rates between 10−16 and 10−14 s−1. Shear stresses larger than 200 MPa can already cause strain localization. The results indicate that thermal softening is a feasible mechanism for spontaneous ductile shear zone generation in the lithosphere and may be one of the primary mechanisms of lithospheric strain localization.
SUMMARY
We present 2-D numerical simulations of convergence at a hyperextended passive margin with exhumed subcontinental mantle. We consider viscoelasto-plastic deformation, heat transfer and ...thermomechanical coupling by shear heating and associated thermal softening due to temperature dependent viscosity. The simulations show subduction initiation for convergence velocities of 2 cm yr−1, initial Moho temperatures of 525 °C and maximal deviatoric stresses of ca. 800 MPa, around the Moho, prior to localization. Subduction initiates in the region with thinned continental crust and is controlled by a thermally activated ductile shear zone in the mantle lithosphere. The shear zone temperature can be predicted with a recently published analytical expression. The criterion for subduction initiation is a temperature difference of at least 225 °C between predicted temperature and initial Moho temperature. The modelled forced subduction broadly agrees with geological data and reconstructions of subduction during closure of the Piemont-Liguria basin, caused by convergence of the European and Adriatic plates during the Alpine orogeny.
Global navigation satellite systems (GNSSs) and ultra-wideband (UWB) ranging are two central research topics in the field of positioning and navigation. In this study, a GNSS/UWB fusion method is ...investigated in GNSS-challenged environments or for the transition between outdoor and indoor environments. UWB augments the GNSS positioning solution in these environments. GNSS stop-and-go measurements were carried out simultaneously to UWB range observations within the network of grid points used for testing. The influence of UWB range measurements on the GNSS solution is examined with three weighted least squares (WLS) approaches. The first WLS variant relies solely on the UWB range measurements. The second approach includes a measurement model that utilizes GNSS only. The third model fuses both approaches into a single multi-sensor model. As part of the raw data evaluation, static GNSS observations processed with precise ephemerides were used to define the ground truth. In order to extract the grid test points from the collected raw data in the measured network, clustering methods were applied. A self-developed clustering approach extending density-based spatial clustering of applications with noise (DBSCAN) was employed for this purpose. The results of the GNSS/UWB fusion approach show an improvement in positioning performance compared to the UWB-only approach, in the range of a few centimeters to the decimeter level when grid points were placed within the area enclosed by the UWB anchor points. However, grid points outside this area indicated a decrease in accuracy in the range of about 90 cm. The precision generally remained within 5 cm for points located within the anchor points.
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