One of the most surprising predictions of modern quantum theory is that the vacuum of space is not empty. In fact, quantum theory predicts that it teems with virtual particles flitting in and out of ...existence. Although initially a curiosity, it was quickly realized that these vacuum fluctuations had measurable consequences--for instance, producing the Lamb shift of atomic spectra and modifying the magnetic moment of the electron. This type of renormalization due to vacuum fluctuations is now central to our understanding of nature. However, these effects provide indirect evidence for the existence of vacuum fluctuations. From early on, it was discussed whether it might be possible to more directly observe the virtual particles that compose the quantum vacuum. Forty years ago, it was suggested that a mirror undergoing relativistic motion could convert virtual photons into directly observable real photons. The phenomenon, later termed the dynamical Casimir effect, has not been demonstrated previously. Here we observe the dynamical Casimir effect in a superconducting circuit consisting of a coplanar transmission line with a tunable electrical length. The rate of change of the electrical length can be made very fast (a substantial fraction of the speed of light) by modulating the inductance of a superconducting quantum interference device at high frequencies (>10 gigahertz). In addition to observing the creation of real photons, we detect two-mode squeezing in the emitted radiation, which is a signature of the quantum character of the generation process.
MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed ...in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca2+ it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. The MUC2-N aggregates were dissolved by removing Ca2+ and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.
We investigate the dynamical Casimir effect in a coplanar waveguide (CPW) terminated by a superconducting quantum interference device (SQUID). Changing the magnetic flux through the SQUID ...parametrically modulates the boundary condition of the CPW, and thereby, its effective length. Effective boundary velocities comparable to the speed of light in the CPW result in broadband photon generation which is identical to the one calculated in the dynamical Casimir effect for a single oscillating mirror. We estimate the power of the radiation for realistic parameters and show that it is experimentally feasible to directly detect this nonclassical broadband radiation.
We investigate the nonlinear interaction between a squeezed cavity mode and a mechanical mode in an optomechanical system (OMS) that allows us to selectively obtain either a radiation-pressure ...coupling or a parametric-amplification process. The squeezing of the cavity mode can enhance the interaction strength into the single-photon strong-coupling regime, even when the OMS is originally in the weak-coupling regime. Moreover, the noise of the squeezed mode can be suppressed completely by introducing a broadband-squeezed vacuum environment that is phase matched with the parametric amplification that squeezes the cavity mode. This proposal offers an alternative approach to control the OMS using a squeezed cavity mode, which should allow single-photon quantum processes to be implemented with currently available optomechanical technology. Potential applications range from engineering single-photon sources to nonclassical phonon states.
The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the ...1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years.
PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the ...synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C-H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.
Uterus transplantation (UTx) may be the only possible curative treatment for absolute uterine factor infertility, which affects 1 in every 500 females of fertile age. We recently presented the ...6-month results from the first clinical UTx trial, describing nine live-donor procedures. This routine involves complicated surgery and requires potentially harmful immune suppression to prevent rejection. However, tissue engineering applications using biomaterials and stem cells may replace the need for a live donor, and could prevent the required immunosuppressive treatment. To investigate the basic aspects of this, we developed a novel whole-uterus scaffold design for uterus tissue engineering experiments in the rat. Decellularization was achieved by perfusion of detergents and ionic solutions. The remaining matrix and its biochemical and mechanical properties were quantitatively compared from using three different protocols. The constructs were further compared with native uterus tissue composition. Perfusion with Triton X-100/dimethyl sulfoxide/H2O led to a compact, weaker scaffold that showed evidence of a compromised matrix organization. Sodium deoxycholate/dH2O perfusion gave rise to a porous scaffold that structurally and mechanically resembled native uterus better. An innovative combination of two proteomic analyses revealed higher fibronectin and versican content in these porous scaffolds, which may explain the improved scaffold organization. Together with other important protocol-dependent differences, our results can contribute to the development of improved decellularization protocols for assorted organs. Furthermore, our study shows the first available data on decellularized whole uterus, and creates new opportunities for numerous in vitro and in vivo whole-uterus tissue engineering applications.
Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of ...other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2−/− embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2−/− brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfrβ. Tgfβ-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgfβ pathway components, including Tgfβ2, Tgfβr2, Alk5, and integrins αVβ8, were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.
•The transcription factor Foxf2 is expressed specifically in CNS pericytes•Foxf2−/− mice have cerebrovascular defects and fail to develop a blood-brain barrier•Foxf2−/− CNS vasculature has reduced Pdgfrβ and Tgfβ-Smad2/3 signaling•Inactivation of Foxf2 in adult mice leads to breakdown of the blood-brain barrier
Pericytes induce formation of the blood-brain barrier (BBB), but it is not clear why only pericytes in the CNS have this unique capability. Reyahi et al. identify the forkhead transcription factor Foxf2 as being expressed specifically in CNS pericytes and as being required for BBB formation and maintenance.
Shoulder injuries and sports-related shoulder pain are substantial burdens for athletes performing a shoulder loading sport. The burden of shoulder problems in the athletic population highlights the ...need for prevention strategies, effective rehabilitation programs, and a individually based return-to-play (RTP) decision. The purpose of this clinical commentary is to discuss each of these 3 challenges in the sporting shoulder, to assist the professional in: (1) preventing injury; (2) providing evidence-based practice rehabilitation and; (3) to guide the athlete toward RTP. The challenges for injury prevention may be found in the search for (the interaction between) relevant risk factors, develop valid screening tests, and implement feasible injury prevention programmes with maximal adherence from the athletes. Combined analytical and functional testing seems mandatory screening an athlete's performance. Many questions arise when rehabilitating the overhead athlete, from exercise selection, over the value of stretching, toward kinetic chain implementation and progression to high performance training. Evidence-based practice should be driven by the available research, clinical expertise and the patient's expectations. Deciding when to return to sport after a shoulder injury is complex and multifactorial. The main concern in the RTP decision is to minimize the risk of re-injury. In the absence of a “gold standard”, clinicians may rely on general guidelines, based on expert opinion, regarding cutoff values for normal range of motion, strength and function, with attention to risk tolerance and load management.
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