In-Brain Multiphoton Imaging of Vaterite Cargoes Loaded with Carbon Dots.

Biocompatible fluorescent agents are key contributors to the theranostic paradigm by enabling real-time in vivo imaging. This study explores the optical properties of phenylenediamine carbon dots (CDs) and demonstrates their potential for fluorescence imaging in cells and brain blood vessels. The nonlinear absorption cross-section of the CDs was measured and achieved values near 50 Goeppert-Mayer (GM) units with efficient excitation in the 775-895 nm spectral range. Mesoporous vaterite nanoparticles were loaded with CDs to examine the possibility of a biocompatible imaging platform. Efficient one- and two-photon imaging of the CD-vaterite composites uptaken by diverse cells was demonstrated. For an in vivo scenario, CD-vaterite composites were injected into the bloodstream of a mouse, and their flow was monitored within the blood vessels of the brain through a cranial window. These results show the potential of the platform for high-brightness biocompatible imaging with the potential for both sensing and simultaneous drug delivery.

Generating Angular-Varying Time Delays of THz Pulses via Direct Space-to-Time Mapping of Metasurface Structures.

We experimentally demonstrate the generation of double terahertz (THz) pulses with tailored angular-dependent time delays from a nonlinear metasurface excited by a near-infrared femtosecond pulse. The tailored temporal properties of the generated pulses emerge from a direct mapping of the nonlinear spatial response of the metasurface to the emitted THz temporal profile. We utilize the Pancharatnam-Berry phase to implement symmetric and antisymmetric metasurface configurations and show that the emitted patterns present spatiotemporal "X-shaped" profiles after collimation by a parabolic mirror, with angular-dependent pulse delays corresponding to the intended design. In addition, we show that the addition of polarization multiplexing presents the opportunity to achieve a full range of elliptical THz polarizations. Double pulse generation and spatiotemporal shaping of THz waves in general show potential for THz spectroscopy and molecular dynamics applications, particularly in pump-probe experiments.

Nonlinear THz Generation through Optical Rectification Enhanced by Phonon-Polaritons in Lithium Niobate Thin Films.

We investigate nonlinear THz generation from lithium niobate films and crystals of different thicknesses by optical rectification of near-infrared femtosecond pulses. A comparison between numerical studies and polarization-resolved measurements of the generated THz signal reveals a 2 orders of magnitude enhancement in the nonlinear response compared to optical frequencies. We show that this enhancement is due to optical phonon modes at 4.5 and 7.45 THz and is most pronounced for films thinner than 2 µm where optical-to-THz conversion is not limited by self-absorption. These results shed new light on the employment of thin film lithium niobate platforms for the development of new integrated broadband THz emitters and detectors. This may also open the door for further control (e.g., polarization, directivity, and spectral selectivity) of the process in nanophotonic structures, such as nanowires and metasurfaces, realized in the thin film platform. We illustrate this potential by numerically investigating optical-to-THz conversion driven by localized surface phonon-polariton resonances in sub-wavelength lithium niobate rods.

Holographic THz Beam Generation by Nonlinear Plasmonic Metasurface Emitters.

The advancement of terahertz (THz) technology hinges on the progress made in the development of efficient sources capable of generating and shaping the THz emission. However, the currently available THz sources provide limited control over the generated field. Here, we use near-field interactions in nonlinear Pancharatnam-Berry phase plasmonic metasurfaces to achieve deep subwavelength, precise, and continuous control over the local amplitude of the emitted field. We show that this new ability can be used for holographic THz beam generation. Specifically, we demonstrate the generation of precisely shaped Hermite-Gauss, Top-Hat, and triangular beams. We show that using this method, higher-order modes are completely suppressed, indicating optimal nonlinear diffraction efficiency. In addition, we demonstrate the application of the generated structured beams for obtaining enhanced imaging resolution and contrast. These demonstrations hold immense potential to address challenges associated with a broad range of new applications employing THz technology.

Electrically and all-optically switchable nonlocal nonlinear metasurfaces.

Nonlocal effects on metasurfaces play an important role to achieve high-Q spectral selectivity, beneficial for development of multifunctional, multispectral integrated optics. In addition, they enhance the optical interaction and promote a variety of nonlinear effects, including frequency conversion and stimulated scattering. Active tuning of nonlocal nonlinearity is highly desirable for sensing and signal processing but was hardly explored until now. Here, we show drastic electric and all-optical tunability of nonlocal second-harmonic generation (SHG) from nonlinear metasurface, functionalized with a twisted nematic liquid-crystal (LC) layer. The addition of LC results in the emergence of strong nonlocal SHG, due to a surface lattice resonance of the system. We demonstrate a notable enhancement of SHG on resonance, more than 25 dB electrical switching amplitude, and all-optically induced phase transition imprinted on SHG. Our results on dynamic nonlocal effects introduce a very promising route for active nonlinear optical metadevices at the nanoscale.

Organic Kainate Single Crystals for Second-Harmonic and Broadband THz Generation.

Organic crystals with unique nonlinear optical properties have been attracting attention owing to their capability to outperform their conventional nonorganic counterparts. Since nonlinear material responses are linked to a crystal's internal microscopic structure, molecular engineering of maximally unharmonic quantum potentials can boost macromolecular susceptibilities. Here, large-scale kainic acid (kainate) single crystals were synthesized, and their linear and nonlinear optical properties were studied in a broad spectral range, spanning the visible to THz spectral regions. The non-centrosymmetric zwitterionic crystallization, molecular structure, and intermolecular arrangement were found to act as additive donor-acceptor domains, enhancing the efficiency of the intrinsic second-order optical nonlinearity of this pure enantiomeric crystal. Molecular simulations and experimental analysis were performed to retrieve the crystals' properties. The crystals were predicted and found to have good transparency in a broad spectral range from the UV to the infrared (0.2-20 µm). Second-harmonic generation was measured for ultrashort pumping wavelengths between 800 and 2400 nm, showing an enhanced response around 600 nm. Broadband THz generation was demonstrated with a detection limited bandwidth of >8 THz along with emission efficiencies comparable to and prevailing those of commercial ZnTe crystals. The broadband nonlinear response and high transparency make kainate crystals extremely attractive for realizing a range of nonlinear optical devices.

THz Radiation Efficiency Enhancement from Metal-ITO Nonlinear Metasurfaces.

Strong single-cycle THz emission has been demonstrated from nonlinear plasmonic metasurfaces, when excited by femtosecond laser pulses. In order to invoke a higher nonlinear response, such metasurfaces have been coupled to thin indium-tin-oxide (ITO) films, which exhibit an epsilon-near zero (ENZ) behavior in the excitation wavelength range and enhance the nonlinear conversion. However, the THz conductivity of the ITO film also reduces the radiation efficiency of the meta-atoms constituting the metasurface. To overcome this, we etch the ITO layer around the plasmonic meta-atoms, which allows harnessing of the enhanced localized fields due to the ENZ behavior of the remaining ITO film, while improving the THz radiation efficiency. We report an increase of more than 1 order of magnitude in the emitted THz spectral power density, while the energy conversion efficiency approaches 10-6. This simple yet very effective fabrication scheme provides important progress toward increasing the range of applications of nonlinear plasmonic metasurface THz emitters.

Terahertz Metagrating Emitters with Beam Steering and Full Linear Polarization Control.

We report the realization of broadband THz plasmonic metagrating emitters for simultaneous beam steering and all-optical linear polarization control. Two types of metagratings are designed and experimentally demonstrated. First, the plasmonic meta-atoms are arranged in a metagrating with a binary phase modulation which results in the nonlinear generation of THz waves to the ±1 diffraction orders, with complete suppression of the zeroth order. Complete tunability of the diffracted THz linear polarization direction is demonstrated through simple rotation of the pump polarization. Then, the concept of lateral phase shift is introduced into the design of the metagratings using interlaced phase gradients. By controlling the spatial shift of the submetagrating, we are able to continuously control the linear polarization states of the generated THz waves. This method results in a higher nonlinear diffraction efficiency relative to binary phase modulation. These functional THz metagratings show exciting promise to meet the challenges associated with the current diverse array of applications utilizing THz technology.

Functional THz emitters based on Pancharatnam-Berry phase nonlinear metasurfaces.

Recent advances in the science and technology of THz waves show promise for a wide variety of important applications in material inspection, imaging, and biomedical science amongst others. However, this promise is impeded by the lack of sufficiently functional THz emitters. Here, we introduce broadband THz emitters based on Pancharatnam-Berry phase nonlinear metasurfaces, which exhibit unique optical functionalities. Using these new emitters, we experimentally demonstrate tunable linear polarization of broadband single cycle THz pulses, the splitting of spin states and THz frequencies in the spatial domain, and the generation of few-cycle pulses with temporal polarization dispersion. Finally, we apply the ability of spin control of THz waves to demonstrate circular dichroism spectroscopy of amino acids. Altogether, we achieve nanoscale and all-optical control over the phase and polarization states of the emitted THz waves.

The Immunoregulatory Activities of Activated Protein C in Inflammatory Disease.

Tissue injury prompts the initiation of host defense responses to limit blood loss, restrict pathogen entry, and promote repair. Biochemical and cellular pathways that lead to blood coagulation serve a fundamental role in generating a physical barrier at the wound site, but have also evolved to promote immune response to injury. Similarly, anticoagulant pathways that attenuate clot formation also regulate innate and adaptive immune responses. Of particular importance is activated protein C (APC) which serves as a principal regulator of thrombin generation, shapes the innate immune response to infection, and has been shown to contribute to the adaptive immune response in several preclinical models of autoimmune disease. APC controls blood coagulation by proteolytic degradation of procoagulant activated cofactors essential for fibrin clot development, but also cleaves multiple additional substrates and interacts with cell surface receptors to exert additional physiologically important roles. In this review, we focus on the molecular mechanisms utilized by APC to limit inflammation and, in particular, current understanding of the basis for APC anticoagulant and signaling activities. In particular, we provide an overview of established and emerging signaling pathways initiated by APC on endothelial cells, monocytes, neutrophils, dendritic cells, and T cells to control and regulate immune cell physiology. Finally, we consider the impact of APC activity in the context of both acute and chronic inflammatory disease, and the continuing efforts to harness the immunoregulatory properties of recombinant APC for therapeutic use.

Staphylococcus aureus-mediated blood-brain barrier injury: an in vitro human brain microvascular endothelial cell model.

Blood-brain barrier (BBB) disruption constitutes a hallmark event during pathogen-mediated neurological disorders such as bacterial meningitis. As a prevalent opportunistic pathogen, Staphylococcus aureus (SA) is of particular interest in this context, although our fundamental understanding of how SA disrupts the BBB is very limited. This paper employs in vitro infection models to address this. Human brain microvascular endothelial cells (HBMvECs) were infected with formaldehyde-fixed (multiplicity of infection [MOI] 0-250, 0-48 hr) and live (MOI 0-100, 0-3 hr) SA cultures. Both Fixed-SA and Live-SA could adhere to HBMvECs with equal efficacy and cause elevated paracellular permeability. In further studies employing Fixed-SA, infection of HBMvECs caused dose-dependent release of cytokines/chemokines (TNF-α, IL-6, MCP-1, IP-10, and thrombomodulin), reduced expression of interendothelial junction proteins (VE-Cadherin, claudin-5, and ZO-1), and activation of both canonical and non-canonical NF-κB pathways. Using N-acetylcysteine, we determined that these events were coupled to the SA-mediated induction of reactive oxygen species (ROS) within HBMvECs. Finally, treatment of HBMvECs with Fixed-ΔSpA (MOI 0-250, 48 hr), a gene deletion mutant of Staphylococcal protein A associated with bacterial infectivity, had relatively similar effects to Newman WT Fixed-SA. In conclusion, these findings provide insight into how SA infection may activate proinflammatory mechanisms within the brain microvascular endothelium to elicit BBB failure.

Dysregulation of the endothelium following Staphylococcus aureus infection.

The cardiovascular system is typically a sterile environment; however entry of a microorganism into the circulation can cause potentially life threatening cardiac and/or vascular disease. Staphylococcus aureus endothelial cell interactions are arguably the most important interactions in the pathogenesis of cardiovascular infection. These interactions can trigger cardiac valve destruction in the case of endocarditis, multi-organ dysfunction in the case of sepsis and coagulopathy. Here, we review the interactions between S. aureus and endothelial cells and discuss the implications of these interactions in the progression of cardiovascular infection.

Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection.

Staphylococcus aureus is the major pathogen among the staphylococci and the most common cause of bone infections. These infections are mainly characterized by bone destruction and inflammation, and are often debilitating and very difficult to treat. Previously we demonstrated that S. aureus protein A (SpA) can bind to osteoblasts, which results in inhibition of osteoblast proliferation and mineralization, apoptosis, and activation of osteoclasts. In this study we used small interfering RNA (siRNA) to demonstrate that osteoblast tumour necrosis factor receptor-1 (TNFR-1) is responsible for the recognition of and binding to SpA. TNFR-1 binding to SpA results in the activation of nuclear factor kappa B (NFκB). In turn, NFκB translocates to the nucleus of the osteoblast, which leads to release of interleukin 6 (IL-6). Silencing TNFR-1 in osteoblasts or disruption of the spa gene in S. aureus prevented both NFκB activation and IL-6 release. As well as playing a key role in proinflammatory reactions, IL-6 is also an important osteotropic factor. Release of IL-6 from osteoblasts results in the activation of the bone-resorbing cells, the osteoclasts. Consistent with our results described above, both silencing TNFR-1 in osteoblasts and disruption of spa in S. aureus prevented osteoclast activation. These studies are the first to demonstrate the importance of the TNFR-1-SpA interaction in bone infection, and may help explain the mechanism through which osteoclasts become overactivated, leading to bone destruction. Anti-inflammatory drug therapy could be used either alone or in conjunction with antibiotics to treat osteomyelitis or for prophylaxis in high-risk patients.