Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward ...these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the “education” of NK cells to achieve functional competence during their maturation and the discovery of “memory” responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.
Carbene-metal-amides are soluble and thermally stable materials which have recently emerged as emitters in high-performance organic light-emitting diodes. Here we synthesise carbene-metal-amide ...photoemitters with CF
-substituted ligands to show sky-blue to deep-blue photoluminescence from charge-transfer excited states. We demonstrate that the emission colour can be adjusted from blue to yellow and observe that the relative energies of charge transfer and locally excited triplet states influence the performance of the deep-blue emission. High thermal stability and insensitivity to aggregation-induced luminescence quenching allow us to fabricate organic light-emitting diodes in both host-free and host-guest architectures. We report blue devices with a peak external quantum efficiency of 17.3% in a host-free emitting layer and 20.9% in a polar host. Our findings inform the molecular design of the next generation of stable blue carbene-metal-amide emitters.
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to ...highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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•Epithelial NOTCH1 signaling drives metastasis in serrated CRC•Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1•TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis•Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.
Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this ...population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.
Cardiac mechanics plays a crucial role in atrial and ventricular function, in the regulation of growth and remodelling, in the progression of disease, and the response to treatment. The spatial scale ...of the critical mechanisms ranges from nm (molecules) to cm (hearts) with the fastest events occurring in milliseconds (molecular events) and the slowest requiring months (growth and remodelling). Due to its complexity and importance, cardiac mechanics has been studied extensively both experimentally and through mathematical models and simulation.
Models of cardiac mechanics evolved from seminal studies in skeletal muscle, and developed into cardiac specific, species specific, human specific and finally patient specific calculations. These models provide a formal framework to link multiple experimental assays recorded over nearly 100 years into a single unified representation of cardiac function. This review first provides a summary of the proteins, physiology and anatomy involved in the generation of cardiac pump function. We then describe the evolution of models of cardiac mechanics starting with the early theoretical frameworks describing the link between sarcomeres and muscle contraction, transitioning through myosin-level models to calcium-driven systems, and ending with whole heart patient-specific models.
This study evaluated the family of ECH2O sensors (EC-5 and ECH2O-TE) for measurement of soil moisture content (θ), bulk electrical conductivity (ECb) and temperature for a range of soils, across a ...range of measurement frequencies between 5 and 150MHz. Measurement frequency is one of the primary factors affecting the sensitivity of capacitance sensor measurements to soil variables such as soil texture, electrical conductivity, and temperature. Measurements in both soil and solution demonstrated that the ECH2O EC and TE measurements were accurate. Using a measurement frequency of 70MHz, a single calibration curve was determined for a range of mineral soils, independent of soil salinity, suggesting there might be no need for a soil specific calibration. When combining all data for each soil type, the R2 values remained high (R2=0.98) with little probe to probe variability. After laboratory calibration, the error for θ was about 2%, independent of soil ECb, up to a soil solution EC of about 12dS/m. Our results showed that a single calibration curve could be used for all tested mineral soils, independent of soil salinity. The bulk soil ECb – water content data were excellently described by a polynomial expression. Measurements of temperature sensitivity to soil water content and ECb were sufficiently small. For example, for a temperature change of 10°C, measurements of θ and ECb were affected by about 0.02cm3cm−3 and 0.02dS/m, respectively. Limited sensor calibration requirements are important, when large networks of soil moisture sensors are being deployed. It is concluded that an accurate, cost-effective soil moisture sensor is available that operates at a measurement frequency of 70MHz, with a low sensitivity to confounding soil environmental factors.
Strontium optical lattice clocks have the potential to simultaneously interrogate millions of atoms with a high spectroscopic quality factor of 4 × 1017. Previously, atomic interactions have forced a ...compromise between clock stability, which benefits from a large number of atoms, and accuracy, which suffers from density-dependent frequency shifts. Here we demonstrate a scalable solution that takes advantage of the high, correlated density of a degenerate Fermi gas in a three-dimensional (3D) optical lattice to guard against on-site interaction shifts. We show that contact interactions are resolved so that their contribution to clock shifts is orders of magnitude lower than in previous experiments. A synchronous clock comparison between two regions of the 3D lattice yields a measurement precision of 5 × 10−19 in 1 hour of averaging time.
Conspectus In this Account, we detail recent progress in wearable bioelectronic devices and discuss the future challenges and prospects of on-body noninvasive bioelectronic systems. Bioelectronics is ...a fast-growing interdisciplinary research field that involves interfacing biomaterials with electronics, covering an array of biodevices, encompassing biofuel cells, biosensors, ingestibles, and implantables. In particular, enzyme-based bioelectronics, built on diverse biocatalytic reactions, offers distinct advantages and represents a centerpiece of wearable biodevices. Such wearable bioelectronic devices predominately rely on oxidoreductase enzymes and have already demonstrated considerable promise for on-body applications ranging from highly selective noninvasive biomarker monitoring to epidermal energy harvesting. These systems can thus greatly increase the analytical capability of wearable devices from the ubiquitous monitoring of mobility and vital signs, toward the noninvasive analysis of important chemical biomarkers. Wearable enzyme electrodes offer exciting opportunities to a variety of areas, spanning from healthcare, sport, to the environment or defense. These include real-time noninvasive detection of biomarkers in biofluids (such as sweat, saliva, interstitial fluid and tears), and the monitoring of environmental pollutants and security threats in the immediate surrounding of the wearer. Furthermore, the interface of enzymes with conducting flexible electrode materials can be exploited for developing biofuel cells, which rely on the bioelectrocatalytic oxidation of biological fuels, such as lactate or glucose, for energy harvesting applications. Crucial for such successful application of enzymatic bioelectronics is deep knowledge of enzyme electron-transfer kinetics, enzyme stability, and enzyme immobilization strategies. Such understanding is critical for establishing efficient electrical contacting between the redox enzymes and the conducting electrode supports, which is of fundamental interest for the development of robust and efficient bioelectronic platforms. Furthermore, stretchable and flexible bioelectronic platforms, with mechanical properties similar to those of biological tissues, are essential for handling the rigors of on-body operation. As such, special attention must be given to changes in the behavior of enzymes due to the uncontrolled conditions of on-body operation (including diverse outdoor activities and different biofluids), for maintaining the attractive performance that these bioelectronics devices display in controlled laboratory settings. Therefore, a focus of this Account is on interfacing biocatalytic layers onto wearable electronic devices for creating efficient and stable on-body electrochemical biosensors and biofuel cells. With proper attention to key challenges and by leveraging the advantages of biocatalysis, electrochemistry, and flexible electronics, wearable bioelectronic devices could have a tremendous impact on diverse biomedical, fitness, and defense fields.
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