Abstract Glucocorticoid hormones (cortisol and corticosterone - CORT) are the effector hormones of the hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system. CORT is a systemic ...intercellular signal whose level predictably varies with time of day and dynamically increases with environmental and psychological stressors. This hormonal signal is utilized by virtually every cell and physiological system of the body to optimize performance according to circadian, environmental and physiological demands. Disturbances in normal HPA axis activity profiles are associated with a wide variety of physiological and mental health disorders. Despite numerous studies to date that have identified molecular, cellular and systems-level glucocorticoid actions, new glucocorticoid actions and clinical status associations continue to be revealed at a brisk pace in the scientific literature. However, the breadth of investigators working in this area poses distinct challenges in ensuring common practices across investigators, and a full appreciation for the complexity of a system that is often reduced to a single dependent measure. This Users Guide is intended to provide a fundamental overview of conceptual, technical and practical knowledge that will assist individuals who engage in and evaluate HPA axis research. We begin with examination of the anatomical and hormonal components of the HPA axis and their physiological range of operation. We then examine strategies and best practices for systematic manipulation and accurate measurement of HPA axis activity. We feature use of experimental methods that will assist with better understanding of CORT's physiological actions, especially as those actions impact subsequent brain function. This research approach is instrumental for determining the mechanisms by which alterations of HPA axis function may contribute to pathophysiology.
Heart failure is a common, costly, and debilitating syndrome that is associated with a highly complex drug regimen, a large number of comorbidities, and a large and often disparate number of ...healthcare providers. All of these factors conspire to increase the risk of heart failure exacerbation by direct myocardial toxicity, drug-drug interactions, or both. This scientific statement is designed to serve as a comprehensive and accessible source of drugs that may cause or exacerbate heart failure to assist healthcare providers in improving the quality of care for these patients.
The Third International Consensus Definitions (Sepsis-3) Task Force recommended the use of the quick Sequential Sepsis-related Organ Failure Assessment (qSOFA) score to screen patients for sepsis ...outside of the ICU. However, subsequent studies raise concerns about the sensitivity of qSOFA as a screening tool. We aim to use machine learning to develop a new sepsis screening tool, the Risk of Sepsis (RoS) score, and compare it with a slate of benchmark sepsis-screening tools, including the Systemic Inflammatory Response Syndrome, Sequential Organ Failure Assessment (SOFA), qSOFA, Modified Early Warning Score, and National Early Warning Score.
We used retrospective electronic health record data from adult patients who presented to 49 urban community hospital emergency departments during a 22-month period (N=2,759,529). We used the Rhee clinical surveillance criteria as our standard definition of sepsis and as the primary target for developing our model. The data were randomly split into training and test cohorts to derive and then evaluate the model. A feature selection process was carried out in 3 stages: first, we reviewed existing models for sepsis screening; second, we consulted with local subject matter experts; and third, we used a supervised machine learning called gradient boosting. Key metrics of performance included alert rate, area under the receiver operating characteristic curve, sensitivity, specificity, and precision. Performance was assessed at 1, 3, 6, 12, and 24 hours after an index time.
The RoS score was the most discriminant screening tool at all time thresholds (area under the receiver operating characteristic curve 0.93 to 0.97). Compared with the next most discriminant benchmark (Sequential Organ Failure Assessment), RoS was significantly more sensitive (67.7% versus 49.2% at 1 hour and 84.6% versus 80.4% at 24 hours) and precise (27.6% versus 12.2% at 1 hour and 28.8% versus 11.4% at 24 hours). The sensitivity of qSOFA was relatively low (3.7% at 1 hour and 23.5% at 24 hours).
In this retrospective study, RoS was more timely and discriminant than benchmark screening tools, including those recommend by the Sepsis-3 Task Force. Further study is needed to validate the RoS score at independent sites.
•Memory function is fundamentally regulated by the circadian system.•Cellular clocks are a genetic timekeeping mechanism underlying circadian rhythms.•Cellular clocks are found locally in brain ...regions that support memory.•Local clocks in the brain directly regulate mechanisms of synaptic plasticity.•Local clocks may optimize memory phasing by modulating neuronal plastic capacity.
The circadian system is an endogenous biological network responsible for coordinating near-24-h cycles in behavior and physiology with daily timing cues from the external environment. In this review, we explore how the circadian system regulates memory formation, retention, and recall. Circadian rhythms in these memory processes may arise through several endogenous pathways, and recent work highlights the importance of genetic timekeepers found locally within tissues, called local clocks. We evaluate the circadian memory literature for evidence of local clock involvement in memory, identifying potential nodes for direct interactions between local clock components and mechanisms of synaptic plasticity. Our discussion illustrates how local clocks may pervasively modulate neuronal plastic capacity, a phenomenon that we designate here as circadian metaplasticity. We suggest that this function of local clocks supports the temporal optimization of memory processes, illuminating the potential for circadian therapeutic strategies in the prevention and treatment of memory impairment.
Here we present plasmon-resonant vibrational sum frequency generation spectroscopy for use in electrochemical measurements. Using surface plasmon resonance we couple light through a CaF2 prism to Au ...films of >50 nm in order to reach the buried Au/electrolyte interface. The approach enables us to use bulk electrolyte, and high current densities (>1 mA/cm2), and therefore is suitable to probe active intermediates under relevant electrochemical reaction conditions. Fresnel factor modeling of the plasmon resonance for a three layer system (CaF2/Au/electrolyte) shows good agreement with experimental data. Off-angle momentum-matching to the surface plasmon resonance allows us to measure functional groups (−CH, −CD, −CN, −NO2) across a wide range of infrared frequencies by simply scanning the infrared wavelength without any angular realignment. Additionally we report a detection limit <1% of a monolayer for the Au/electrolyte interface. Using this method we observe an active intermediate during CO2 reduction on Au at catalytic currents. Consequently, we believe that this method will provide mechanistic understanding of electrochemical reactions.
Matrix stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and ...correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Recent evidence has shown that, in addition to rigidity, the viscous response of the extracellular matrix (ECM) significantly affects the behavior and function of cells. However, the mechanism behind ...such mechanosensitivity toward viscoelasticity remains unclear. In this study, we systematically examined the dynamics of motor clutches (i.e., focal adhesions) formed between the cell and a viscoelastic substrate using analytical methods and direct Monte Carlo simulation. Interestingly, we observe that, for low ECM rigidity, maximum cell spreading is achieved at an optimal level of viscosity in which the substrate relaxation time falls between the timescale for clutch binding and its characteristic binding lifetime. That is, viscosity serves to stiffen soft substrates on a timescale faster than the clutch off-rate, which enhances cell–ECM adhesion and cell spreading. On the other hand, for substrates that are stiff, our model predicts that viscosity will not influence cell spreading, since the bound clutches are saturated by the elevated stiffness. The model was tested and validated using experimental measurements on three different material systems and explained the different observed effects of viscosity on each substrate. By capturing the mechanism by which substrate viscoelasticity affects cell spreading across a wide range of material parameters, our analytical model provides a useful tool for designing biomaterials that optimize cellular adhesion and mechanosensing.
The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well ...characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.
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•C-Raf binds all Ras proteins equivalently, but B-Raf exhibits selectivity for K-Ras•Raf N-terminal segments and Ras HVR sequences determine binding preferences•C-Raf is critical for downstream transmission of H-Ras-driven signaling•Events that increase B-Raf/C-Raf dimerization augment the B-Raf/H-Ras interaction
The Raf kinases bind to active Ras proteins and function to transmit signals that control cell growth and tumorigenesis. The study by Terrell et al. reveals distinct binding preferences between individual Ras and Raf family members and identifies events that can alter these interactions to upregulate Ras-driven cancer signaling.
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