The North Atlantic Oscillation (NAO) is a dominant atmospheric variability in the Northern Hemisphere that has a substantial impact on weather and climate on various time scales. Here, we investigate ...the role of energy conversion terms day‐by‐day during the NAO life cycle. The relative timing and contribution of the energy conversion terms are quantified by projecting the terms onto the eddy total energy, eddy kinetic energy (EKE), and eddy available potential energy (EAPE) patterns associated with the NAO. The results show a remarkable phase dependence in the growth and maintenance mechanisms. For positive NAOs, the initial growth is driven by the barotropic interactions between the eddies propagating over North America. This suggests that a non‐local growth mechanism plays an important role in the initiation of positive NAOs. In contrast, it is the baroclinic processes that initiate negative NAOs. The conversion of the mean APE into the EAPE and then into the EKE, processes which include eddy heat fluxes and vertical motions, results in the relatively local growth of negative NAOs. During the mature phase, the largest source of energy is the conversion of the mean APE into EAPE. Part of this is converted to EKE, making a substantial contribution to the maintenance of the EKE. This process is particularly important for negative NAOs.
Here the daily energy cycles of the North Atlantic Oscillation (NAO) during the boreal winter are examined using budget analysis on the energy tendency equations. We find some phase‐dependent process in the energetics of the NAO phases. The positive NAO events are driven by the barotropic process, whereas the negative NAO events are initiated by the baroclinic processes. Such a difference stems from the relative position of the NAO to the background state.
More than half of the adult population worldwide is overweight or obese, while excess adiposity has been linked to chronic low-grade inflammation, contributing to the development of chronic diseases. ...Recent studies have showed that diet-induced alterations to the gut microbiota composition play a pivotal role in the development of obesity. However, the cause-effect relationship between obesity and gut microbiota composition is not yet fully understood. In this study, we investigated the short-term responses of gut microbiota composition to diets with different fat contents and their associations with inflammatory biomarkers.
Sixty male C57BL/6 J mice were fed a normal diet (ND; 15% fat) or a high-fat diet (HFD; 45% fat) for 10 or 20 weeks. The relative proportion of the phylum Actinobacteria was elevated by the HFD and was positively associated with body weight and proinflammatory cytokines including TNF-α, IL-1β, and IL-6. The proportion of the phylum Firmicutes increased with aging and was also positively correlated with proinflammatory cytokines. The proportions of Actinobacteria and Firmicutes were inversely associated with tight junction proteins claudin-1 and E-cadherin, respectively. The proportions of the class Clostridia and the family Ruminococcaceae within the phylum Firmicutes were affected by both diet and age. In addition, the proportions of the phylum Bacteroidetes, the family Bacteroidaceae, and the genus Bacteroides decreased with aging and were inversely correlated with colonic proinflammatory cytokines representing a positive association with tight junction proteins.
Host age and dietary fat intake are important elements that induce proportional changes in gut microbiota, and these changes are also associated with systemic inflammation. This study provides evidence that diet affects the gut microbiota composition within a short period of time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. ...Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug's mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.
Bioresorbable electronic systems represent an emerging class of technology of interest due to their ability to dissolve, chemically degrade, disintegrate, and/or otherwise physically disappear ...harmlessly in biological environments, as the basis for temporary implants that avoid the need for secondary surgical extraction procedures. Polyanhydride‐based polymers can serve as hydrophobic encapsulation layers for such systems, as a subset of the broader field of transient electronics, where biodegradation eventually occurs by chain scission. Systematic experimental studies that involve immersion in phosphate‐buffered saline solution at various pH values and/or temperatures demonstrate that dissolution occurs through a surface erosion mechanism, with little swelling. The mechanical properties of this polymer are well suited for use in soft, flexible devices, where integration can occur through a mold‐based photopolymerization technique. Studies of the dependence of the polymer properties on monomer compositions and the rates of permeation on coating thicknesses reveal some of the underlying effects. Simple demonstrations illustrate the ability to sustain operation of underlying biodegradable electronic systems for durations between a few hours to a week during complete immersion in aqueous solutions that approximate physiological conditions. Systematic chemical, physical, and in vivo biological studies in animal models reveal no signs of toxicity or other adverse biological responses.
Synthetic procedures, degradation kinetics, water absorption properties, and water barrier characteristics of bioresorbable polyanhydride are presented. This polymer, as encapsulation layers in water‐soluble electronic devices, can be used to define the functional lifetimes by controlling the coating thickness and polymer chemistry. In vitro permeability encapsulation and in vivo biocompatibility studies support the potential use of this material in temporary biomedical implants with designs for both acute and chronic operation.
A novel ultra-short-acting benzodiazepine (BDZ), remimazolam (CNS 7056), has been designed by 'soft drug' development to achieve a better sedative profile than that of the current drugs. Notably, the ...esterase linkage in remimazolam permits rapid hydrolysis to inactivate metabolites by non-specific tissue esterase and induces a unique and favorable pharmacological profile, including rapid onset and offset of sedation and a predictable duration of action. Similar to other BDZs, its sedative effects can be reversed using flumazenil, a BDZ antagonist. The pharmacokinetics and pharmacodynamics of remimazolam are characterized by relatively high clearance, small steady-state volume of distribution, short elimination half-life, short context-sensitive half-life, and fast onset and recovery, indicating rapid elimination, minimal tissue accumulation, and good control. In addition, remimazolam possesses a superior safety profile, including low liability for cardiorespiratory depression and injection pain, making it a preferred hypnotic agent in various clinical settings. Early clinical investigations suggest that remimazolam is well tolerated and effective for procedural sedation and for induction and maintenance of general anesthesia. To date, however, the clinical use of remimazolam has been confined to a few volunteer studies and a limited number of clinical investigations. Therefore, further studies regarding its recovery issues or postoperative complications, characteristics of electroencephalogram changes, and cost-benefit analyses are required to facilitate its widespread use.
This study investigates the origin of the interdecadal variability in the warm Arctic and cold Eurasia (WACE) pattern, which is defined as the second empirical orthogonal function of surface air ...temperature (SAT) variability over the Eurasian continent in Northern Hemisphere winter, by analyzing the Twentieth Century Reanalysis dataset. While previous studies highlight recent enhancement of the WACE pattern, ascribing it to anthropogenic warming, the authors found that the WACE pattern has experienced a seemingly periodic interdecadal variation over the twentieth century. This long-term variation in the Eurasian SAT is attributable to the altered coupling between the Siberian high (SH) and intraseasonal Rossby wave emanating from the North Atlantic, as the local wave branch interacts with the SH and consequentially enhances the continental temperature perturbation. It is further identified that these atmospheric circulation changes in Eurasia are largely controlled by the decadal amplitude modulation of the climatological stationary waves over the North Atlantic region. The altered decadal mean condition of stationary wave components brings changes in local baroclinicity and storm track activity over the North Atlantic, which jointly change the intraseasonal Rossby wave generation and propagation characteristics as well. With simple stationary wave model experiments, the authors confirm how the altered mean flow condition in the North Atlantic acts as a source for the growth of the Rossby wave that leads to the change in the downstream WACE pattern.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. During metastasis, ...tumor cells enter the circulation to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood.
Here, we present both in vivo and in vitro evidence that EMT-like transition also occurs in circulating tumor cells (CTCs) as a result of hydrodynamic shear stress (+SS), which promotes conversion of CD24
/CD44
/CD133
/CXCR4
/ALDH1
primary patient epithelial tumor cells into specific high sphere-forming CD24
/CD44
/CD133
/CXCR4
/ALDH1
cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) with elevated tumor progression and metastasis capacity in vitro and in vivo. We demonstrate that conversion of CSLCs/TICs from epithelial tumor cells via +SS is dependent on reactive oxygen species (ROS)/nitric oxide (NO) generation, and suppression of extracellular signal-related kinase (ERK)/glycogen synthase kinase (GSK)3β, a mechanism similar to that operating in embryonic stem cells to prevent their differentiation while promoting self-renewal.
Fluid shear stress experienced during systemic circulation of human breast tumor cells can lead to specific acquisition of mesenchymal stem cell (MSC)-like potential that promotes EMT, mesenchymal-epithelial transition, and metastasis to distant organs. Our data revealed that biomechanical forces appeared to be important microenvironmental factors that not only drive hematopoietic development but also lead to acquisition of CSLCs/TIC potential in cancer metastasis. Our data highlight that +SS is a critical factor that promotes the conversion of CTCs into distinct TICs in blood circulation by endowing plasticity to these cells and by maintaining their self-renewal signaling pathways.
Cancer immunotherapy has emerged as a promising cancer treatment. However, the presence of immune-refractory tumor cells limits its clinical success by blocking amplification of anti-tumor immunity. ...Previously, we found that immune selection by immunotherapy drives the evolution of tumors toward multi-modal resistant and stem-like phenotypes via transcription induction of AKT co-activator TCL1A by NANOG. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and multi-aggressive properties of immune-edited tumor cells by identifying HSP90AA1 as a NANOG transcriptional target. Furthermore, we demonstrate that HSP90A potentiates AKT activation through TCL1A-stabilization, thereby contributing to the multi-aggressive properties in NANOG
tumor cells. Importantly, HSP90 inhibition sensitized immune-refractory tumor to adoptive T cell transfer as well as PD-1 blockade, and re-invigorated the immune cycle of tumor-reactive T cells. Our findings implicate that the HSP90A-TCL1A-AKT pathway ignited by NANOG is a central molecular axis and a potential target for immune-refractory tumor.
Abstract
Energetics of the major atmospheric teleconnection patterns of the Northern Hemisphere winter are examined to investigate the role of baroclinic and barotropic energy conversions in their ...growth. Based on characteristics of the energetics and the horizontal structures, the patterns are classified into three general types: meridional dipole (D-type), wave (W-type), and hybrid (H-type). The primary energy conversion term that differentiates these patterns is the baroclinic energy conversion of the available potential energy from the climatology to the eddy field associated with the teleconnections. For this conversion term, D-type patterns exhibit the comparable conversion of potential energy via the eddy heat flux across the climatological thermal gradient in both the zonal and meridional directions. In contrast, baroclinic conversion for W-type patterns occurs primarily in the meridional direction, while H-type patterns exhibit a structure that combines the characteristics of the other two pattern types. An important secondary factor is barotropic conversion from the climatology to the eddy field, which takes place mainly in the regions where the climatological shear is strong. For the D-type patterns, conversion occurs on the flank of the climatological jet exit, while it occurs at the center of the jet exit for the W-type patterns. Last, for all the patterns, synoptic-time-scale eddies make a negative contribution via the baroclinic process, but a positive contribution via the barotropic process. Damping by diabatic heating weakens the temperature anomalies associated with the patterns.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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