Femtosecond laser-based generation of radio frequency signals has produced astonishing improvements in achievable spectral purity, one of the basic features characterizing the performance of an radio ...frequency oscillator. Kerr frequency combs hold promise for transforming these lab-scale oscillators to chip-scale level. In this work we demonstrate a miniature 10 GHz radio frequency photonic oscillator characterized with phase noise better than -60 dBc Hz(-1) at 10 Hz, -90 dBc Hz(-1) at 100 Hz and -170 dBc Hz(-1) at 10 MHz. The frequency stability of this device, as represented by Allan deviation measurements, is at the level of 10(-10) at 1-100 s integration time-orders of magnitude better than existing radio frequency photonic devices of similar size, weight and power consumption.
Advanced applications in optical metrology demand improved lasers with high spectral purity, in form factors that are small and insensitive to environmental perturbations. While laboratory-scale ...lasers with extraordinarily high stability and low noise have been reported, all-integrated chip-scale devices with sub-100 Hz linewidth have not been previously demonstrated. Lasers integrated with optical microresonators as external cavities have the potential for substantial reduction of noise. However, stability and spectral purity improvements of these lasers have only been validated with rack-mounted support equipment, assembled with fibre lasers to marginally improve their noise performance. In this work we report on a realization of a heterogeneously integrated, chip-scale semiconductor laser featuring 30-Hz integral linewidth as well as sub-Hz instantaneous linewidth.
The molar mass of water vapor is much less than that of dry air. This makes a moist parcel lighter than a dry parcel of the same temperature and pressure. This effect is referred to as the vapor ...buoyancy effect and has often been overlooked in climate studies. We propose that the vapor buoyancy effect increases Earth’s outgoing longwave radiation (OLR) and that this negative radiative effect increases with warming, stabilizing Earth’s climate. We illustrate this mechanism in an idealized tropical atmosphere, where there is no horizontal buoyancy gradient in the free troposphere. Temperature increases toward dry atmosphere columns to compensate the reduced vapor buoyancy, increasing OLR by O(1 W m−2) at the reference climate. In warmer climates, the temperature difference between moist and dry columns would increase as a result of increasing atmospheric water vapor, leading to enhanced radiative effect and thereby stabilizing Earth’s climate. We estimate that this feedback strength is about O(0.2 W m−2 K−1) in the idealized atmosphere, which compares to cloud feedback and surface albedo feedback in the current climate. We further show evidence from observations and real-gas radiative transfer calculations for a significant radiative effect of vapor buoyancy in the tropical atmosphere.
The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge ...for defining the biological contribution of each specific interaction. We developed a strategy for addressing these challenges by combining cell microarray and high-throughput FACS methods to screen for promiscuous binding events, map binding interfaces, and generate functionally selective reagents. Applying this approach to the interactions of mPD-L1 with its receptor mPD-1 and its ligand mB7-1, we identified the binding interface of mB7-1 on mPD-L1 and as a result generated mPD-L1 mutants with binding selectivity for mB7-1 or mPD-1. Next, using a panel of mB7-1 mutants, we mapped the binding sites of mCTLA-4, mCD28 and mPD-L1. Surprisingly, the mPD-L1 binding site mapped to the dimer interface surface of mB7-1, placing it distal from the CTLA-4/CD28 recognition surface. Using two independent approaches, we demonstrated that mPD-L1 and mB7-1 bind in cis, consistent with recent reports from Chaudhri A et al. and Sugiura D et al. We further provide evidence that while CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. These observations offer new functional insights into the regulatory mechanisms associated with this group of B7 family proteins and provide new tools to elucidate their function in vitro and in vivo.
We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
ALK-rearranged stage IIIB/IV NSCLC patients were analyzed ...with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients PFS 3.9months (95% CI: 2.4–5.6) versus 10.3months (95% CI: 8.6–12.0), P<0.001; OS 15.0months (95% CI: 5.0–24.9) versus 50.0months (95% CI: 22.9–77.1), P=0.002. This difference was confirmed in all treatment-related subgroups including chemotherapy only PFS first-line chemotherapy 2.6months (95% CI: 1.3–4.1) versus 6.2months (95% CI: 1.8–10.5), P=0.021; OS 2.0months (95% CI: 0.0–4.6) versus 9.0months (95% CI: 6.1–11.9), P=0.035, crizotinib plus chemotherapy PFS crizotinib 5.0months (95% CI: 2.9–7.2) versus 14.0months (95% CI: 8.0–20.1), P<0.001; OS 17.0months (95% CI: 6.7–27.3) versus not reached, P=0.049 and crizotinib followed by next-generation ALK-inhibitor PFS next-generation inhibitor 5.4months (95% CI: 0.1–10.7) versus 9.9months (95% CI: 6.4–13.5), P=0.039; OS 7.0months versus 50.0months (95% CI: not reached), P=0.001).
In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
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In this work, a coupled electromechanical peridynamics formulation is presented which is used to study the electrical and piezoresistive response of a carbon nanotube (CNT) reinforced ...polymer nanocomposite material. CNT nanocomposites are multiscale materials which have unique piezoresistive properties arising from mechanisms operating from the nanoscale to the macroscale. The origin of piezoresistivity in CNT nanocomposites is a nanoscale phenomenon known as electron hopping or the electrical tunneling effect which allows an electric current to flow between neighboring CNTs even when not in contact, thereby forming a conductive network. A nanoscale representative volume element of a CNT bundle is chosen, i.e. a local region of high CNT volume fraction within the polymer matrix, wherein coupled electromechanical peridynamic equations are solved to evaluate the effective electrical and piezoresistive properties. The peridynamics formulation is used to introduce electron hopping in a unique way, through electron hopping bonds which have a horizon distance and conductivity dictated by the appropriate physics operating at the nanoscale. The effective electromechanical response depends on parameters such as CNT volume fraction, properties of the polymer matrix between CNTs and applied strain which are investigated in detail. Both quasistatic and dynamic loading conditions are considered where the effective electromechanical response is found to depend on variations in the local conductivity of intertube regions.
A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold ...particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients.
CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart.
Doses from 50 μg/m(2) to 600 μg/m(2) were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m(2), did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue.
These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers.
Lewis X (Lex)-containing glycans play important roles in numerous cellular processes. However, the absence of robust, facile, and cost-effective methods for the synthesis of Lex and its structurally ...related analogs has severely hampered the elucidation of the specific functions of these glycan epitopes. Here we demonstrate that chemically defined guanidine 5'-diphosphate-β-L-fucose (GDP-fucose), the universal fucosyl donor, the Lex trisaccharide, and their C-5 substituted derivatives can be synthesized on preparative scales, using a chemoenzymatic approach. This method exploits L-fucokinase/GDP-fucose pyrophosphorylase (FKP), a bifunctional enzyme isolated from Bacteroides fragilis 9343, which converts L-fucose into GDP-fucose via a fucose-1-phosphate (Fuc-1-P) intermediate. Combining the activities of FKP and a Helicobacter pylori α1,3 fucosyltransferase, we prepared a library of Lex trisaccharide glycans bearing a wide variety of functional groups at the fucose C-5 position. These neoglycoconjugates will be invaluable tools for studying Lex-mediated biological processes.
We demonstrate a miniature self-injection locked distributed-feedback laser using resonant optical feedback from a high-Q crystalline whispering-gallery-mode resonator. The linewidth reduction factor ...is greater than 10,000, with resultant instantaneous linewidth of less than 200 Hz. The minimal value of the Allan deviation for the laser-frequency stability is 3 x 10(-12) at the integration time of 20 micros. The laser possesses excellent spectral purity and good long-term stability.
The lymphatic system plays an important role in the physiological control of the tissue fluid balance and in the initiation of immune responses. Recent studies have shown that lymphangiogenesis, the ...growth of new lymphatic vessels and/or the expansion of existing lymphatic vessels, is a characteristic feature of acute inflammatory reactions and of chronic inflammatory diseases. In these conditions, lymphatic vessel expansion occurs at the tissue level but also within the draining lymph nodes. Surprisingly, activation of lymphatic vessel function by delivery of vascular endothelial growth factor-C exerts anti-inflammatory effects in several models of cutaneous and joint inflammation. These effects are likely mediated by enhanced drainage of extravasated fluid and inflammatory cells, but also by lymphatic vessel-mediated modulation of immune responses. Although some of the underlying mechanisms are just beginning to be identified, lymphatic vessels have emerged as important targets for the development of new therapeutic strategies to treat inflammatory conditions. In this context, it is of great interest that some of the currently used anti-inflammatory drugs also potently activate lymphatic vessels.
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