Integrated optical frequency division for microwave and mmWave generation.

The generation of ultra-low-noise microwave and mmWave in miniaturized, chip-based platforms can transform communication, radar and sensing systems1-3. Optical frequency division that leverages optical references and optical frequency combs has emerged as a powerful technique to generate microwaves with superior spectral purity than any other approaches4-7. Here we demonstrate a miniaturized optical frequency division system that can potentially transfer the approach to a complementary metal-oxide-semiconductor-compatible integrated photonic platform. Phase stability is provided by a large mode volume, planar-waveguide-based optical reference coil cavity8,9 and is divided down from optical to mmWave frequency by using soliton microcombs generated in a waveguide-coupled microresonator10-12. Besides achieving record-low phase noise for integrated photonic mmWave oscillators, these devices can be heterogeneously integrated with semiconductor lasers, amplifiers and photodiodes, holding the potential of large-volume, low-cost manufacturing for fundamental and mass-market applications13.

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.

Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.

32-channel wide-bandwidth massive RF photonic combiner based on distributed groups of arrayed photodetectors.

We propose and experimentally demonstrate a low-loss, radio frequency (RF) photonic signal combiner with flat response from 1 GHz to 15 GHz and low group delay variation of 9 ps. The distributed group array photodetector combiner (GAPC) is implemented in a scalable Si photonics platform and has applications in RF photonic systems that rely on combining massive numbers of photonic signals.

All-optical linearized Mach-Zehnder modulator.

A practical, broadband, all-optical linearization concept for a Mach-Zehnder modulator (MZM) is proposed and demonstrated. The unique transmitter design includes an amplitude modulated (AM) standard MZM with two optical outputs, where the alternative (or complimentary) output is combined with the laser carrier to create a linearizing optical local oscillator, which when coherently combined with the AM signal fully cancels 3rd order intermodulation distortion components. Using this scheme, record linearity is achieved for a non-amplified RF photonic link, with spurious free dynamic range (SFDR) of 118.5 dB.Hz2/3 and 123 dB.Hz2/3 for single and dual fiber/photodetector schemes.

Rhodium Indenyl NHC and Fluorenyl-Tethered NHC Half-Sandwich Complexes: Synthesis, Structures and Applications in the Catalytic C-H Borylation of Arenes and Alkanes.

Indenyl (Ind) rhodium N-heterocyclic carbene (NHC) complexes [Rh(η5 -Ind)(NHC)(L)] were synthesised for 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) with L=C2 H4 (1), CO (2 a) and cyclooctene (COE; 3), for 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes) with L=CO (2 b) and COE (4), and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) with L=CO (2 c) and COE (5). Reaction of SIPr with [Rh(Cp*)(C2 H4 )2 ] did not give the desired SIPr complex, thus demonstrating the "indenyl effect" in the synthesis of 1. Oxidative addition of HSi(OEt)3 to 3 proceeded under mild conditions to give the Rh silyl hydride complex [Rh(Ind){Si(OEt)3 }(H)(SIPr)] (6) with loss of COE. Tethered-fluorenyl NHC rhodium complexes [Rh{(η5 -C13 H8 )C2 H4 N(C)C2 Hx NR}(L)] (x=4, R=Dipp, L=C2 H4 : 11; L=COE: 12; L=CO: 13; R=Mes, L=COE: 14; L=CO: 15; x=2, R=Me, L=COE: 16; L=CO: 17) were synthesised in low yields (5-31 %) in comparison to good yields for the monodentate complexes (49-79 %). Compounds 3 and 1, which contain labile alkene ligands, were successful catalysts for the catalytic borylation of benzene with B2 pin2 (Bpin=pinacolboronate, 97 and 93 % PhBpin respectively with 5 mol % catalyst, 24 h, 80 °C), with SIPr giving a more active catalyst than SIMes or IMes. Fluorenyl-tethered NHC complexes were much less active as borylation catalysts, and the carbonyl complexes were inactive. The borylation of toluene, biphenyl, anisole and diphenyl ether proceeded to give meta substitutions as the major product, with smaller amounts of para substitution and almost no ortho product. The borylation of octane and decane with B2 pin2 at 120 and 140 °C, respectively, was monitored by 11 B NMR spectroscopy, which showed high conversions into octyl and decylBpin over 4-7 days, thus demonstrating catalysed sp3 C-H borylation with new piano stool rhodium indenyl complexes. Irradiation of the monodentate complexes with 400 or 420 nm light confirmed the ready dissociation of C2 H4 and COE ligands, whereas CO complexes were inert. Evidence for C-H bond activation in the alkyl groups of the NHC ligands was obtained.

Effects of nonlinear loss in high-Q Si ring resonators for narrow-linewidth III-V/Si heterogeneously integrated tunable lasers.

High-Q Si ring resonators play an important role in the development of widely tunable heterogeneously integrated lasers. However, while a high Q-factor (Q > 1 million) is important for ring resonators in a laser cavity, the parasitic high-power density in a Si resonator can deteriorate the laser performance at high power levels due to nonlinear loss. Here, we experimentally show that this detrimental effect can happen at moderate power levels (a few milliwatts) where typical heterogeneously integrated lasers work. We further compare different ring resonators, including extended Si ring resonators and Si3N4 ring resonators and provide practical approaches to minimize this effect. Our results provide explanations and guidelines for high-Q ring resonator designs in heterogeneously integrated tunable lasers, and they are also applicable for hybrid integrated butt-coupled lasers.

Chip-based soliton microcomb module using a hybrid semiconductor laser.

Photonic chip-based soliton microcombs have shown rapid progress and have already been used in many system-level applications. There has been substantial progress in realizing soliton microcombs that rely on compact laser sources, culminating in devices that only utilize a semiconductor gain chip or a self-injection-locked laser diode as the pump source. However, generating single solitons with electronically detectable repetition rates from a compact laser module has remained challenging. Here we demonstrate a current-initiated, Si3N4 chip-based, 99-GHz soliton microcomb driven directly by a compact, semiconductor-based laser. This approach does not require any complex soliton tuning techniques, and single solitons can be accessed by tuning the laser current. Further, we demonstrate a generic, simple, yet reliable, packaging technique to facilitate the fiber-chip interface, which allows building a compact soliton microcomb package that can benefit from the fiber systems operating at high power (> 100 mW). Both techniques can exert immediate impact on chip-based nonlinear photonic applications that require high input power, high output power, and interfacing chip-based devices to mature fiber systems.

Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury.

Although age-at-injury influences chronic recovery from traumatic brain injury (TBI), the differential effects of age on early outcome remain understudied. Using a male murine model of moderate contusion injury, we investigated the underlying mechanism(s) regulating the distinct response between juvenile and adult TBI. We demonstrate similar biomechanical and physical properties of naive juvenile and adult brains. However, following controlled cortical impact (CCI), juvenile mice displayed reduced cortical lesion formation, cell death, and behavioral deficits at 4 and 14 d. Analysis of high-resolution laser Doppler imaging showed a similar loss of cerebral blood flow (CBF) in the ipsilateral cortex at 3 and 24 h post-CCI, whereas juvenile mice showed enhanced subsequent restoration at 2-4 d compared with adults. These findings correlated with reduced blood-brain barrier (BBB) disruption and increased perilesional vessel density. To address whether an age-dependent endothelial cell (EC) response affects vessel stability and tissue outcome, we magnetically isolated CD31+ ECs from sham and injured cortices and evaluated mRNA expression. Interestingly, we found increased transcripts for BBB stability-related genes and reduced expression of BBB-disrupting genes in juveniles compared with adults. These differences were concomitant with significant changes in miRNA-21-5p and miR-148a levels. Accompanying these findings was robust GFAP immunoreactivity, which was not resolved by day 35. Importantly, pharmacological inhibition of EC-specific Tie2 signaling abolished the juvenile protective effects. These findings shed new mechanistic light on the divergent effects that age plays on acute TBI outcome that are both spatial and temporal dependent.SIGNIFICANCE STATEMENT Although a clear "window of susceptibility" exists in the developing brain that could deter typical developmental trajectories if exposed to trauma, a number of preclinical models have demonstrated evidence of early recovery in younger patients. Our findings further demonstrate acute neuroprotection and improved restoration of cerebral blood flow in juvenile mice subjected to cortical contusion injury compared with adults. We also demonstrate a novel role for endothelial cell-specific Tie2 signaling in this age-related response, which is known to promote barrier stability, is heightened in the injured juvenile vasculature, and may be exploited for therapeutic interventions across the age spectrum following traumatic brain injury.

Ultra-narrow linewidth laser based on a semiconductor gain chip and extended Si3N4 Bragg grating.

We demonstrate ultra-narrow linewidth fixed wavelength hybrid lasers composing a semiconductor gain chip and extended silicon nitride Bragg grating. Fabricated ultra-low κ Bragg gratings provide a narrow bandwidth and high side-lobe suppression ratio. A single-wavelength 1544 nm hybrid extended-distributed Bragg reflector laser with 24 mW output power and a Lorentzian linewidth of 320 Hz is demonstrated, providing a high-performance light source for on- and off-chip applications.

Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation.

In the past 2 decades, it has become evident that individuals born with congenital heart disease (CHD) are at risk of developing life-long neurological deficits. Multifactorial risk factors contributing to neurodevelopmental abnormalities associated with CHD have been identified; however, the underlying causes remain largely unknown, and efforts to address this issue have only recently begun. There has been a dramatic shift in focus from newly acquired brain injuries associated with corrective and palliative heart surgery to antenatal and preoperative factors governing altered brain maturation in CHD. In this review, we describe key time windows of development during which the immature brain is vulnerable to injury. Special emphasis is placed on the dynamic nature of cellular events and how CHD may adversely impact the cellular units and networks necessary for proper cognitive and motor function. In addition, we describe current gaps in knowledge and offer perspectives about what can be done to improve our understanding of neurological deficits in CHD. Ultimately, a multidisciplinary approach will be essential to prevent or improve adverse neurodevelopmental outcomes in individuals surviving CHD.

Phase tuning by length contraction.

Typical integrated optical phase tuners alter the effective index. In this paper, we explore tuning by geometric deformation. We show that tuning efficiency, Vπ L, improves as the device size shrinks down to the optimal bend radius, contrary to conventional index-shift based approaches where Vπ L remains constant. We demonstrate that this approach is capable of ultra-low power tuning across a full FSR in a low-confinement silicon nitride based ring resonator of 580 µm radius. We demonstrate record performance with VFSR = 16 V, Vπ L = 3.6 V dB, Vπ Lα = 1.1 V dB, tuning current below 10 nA, and unattenuated tuning response up to 1 MHz. We also present optimized designs for high confinement silicon nitride and silicon based platforms with radius down to 80 µm and 45 µm, respectively, with performance well beyond current state-of-the-art. Applications include narrow-linewidth tunable diode lasers for spectroscopy and non-linear optics, optical phased array beamforming networks for RF antennas and LIDAR, and optical filters for WDM telecommunication links.

Integrated broadband Ce:YIG/Si Mach-Zehnder optical isolators with over 100 nm tuning range.

We demonstrate integrated optical isolators with broadband behavior for the standard silicon-on-insulator platform. We achieve over 20 dB of optical isolation across 18 nm of optical bandwidth. The isolator is completely electrically controlled and does not require a permanent magnet. Furthermore, we demonstrate the ability to tune the central operating wavelength of the isolator across 100 nm, which covers the entire S + C telecom bands. These devices show promise for integration in optical systems in which broadband isolation is needed such as wavelength multiplexed systems or optical sensors.

Highly linear heterogeneous-integrated Mach-Zehnder interferometer modulators on Si.

In this paper we demonstrate highly linear Mach-Zehnder interferometer modulators utilizing heterogeneous integration on a Si substrate (HS-MZM). A record high dynamic range was achieved for silicon devices, obtained using hybrid III-V/Si phase modulation sections and single drive push-pull operation, demonstrating a spurious free dynamic range (SFDR) of 112 dB∙Hz2/3 at 10 GHz, comparable to commercial Lithium Niobate MZMs.

Low kappa, narrow bandwidth Si(3)N(4) Bragg gratings.

We investigate three approaches to low perturbation gratings to achieve lower linewidths in filters and semiconductor lasers. The three designs, which are labeled post, sampled, and high order, are DUV lithography compatible and were fabricated on 90 nm thick Si(3)N(4) strip waveguides. Reflection and transmission spectra measurements show coupling constant, kappa, values ranging from 0.23 cm(­1) to 1.2 cm(­1) with FWHM values of 74 pm to 116 pm. We discuss the tradeoffs between these geometries in terms of lowest linewidth, apodization, and curved waveguide layout. These results enable long cavity single mode lasers with kHz level linewidths on a monolithic platform.

Activation of NF-κB in Schwann cells is dispensable for myelination in vivo.

Peripheral myelination is a dynamic process orchestrated by axons and Schwann cells. Although the signaling mechanisms governing myelination are not fully understood, NF-κB activation in Schwann cells has been implicated as a key regulator in vitro. Using a mouse model, we show that nuclear factor κB activation in Schwann cells is not required for myelination in vivo.

Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination.

Astrocytes respond to insult with a process of cellular activation known as reactive astrogliosis. One of the key signals regulating this phenomenon is the transcription factor nuclear factor-kappa B (NF-κB), which is responsible for modulating inflammation, cell survival, and cell death. In astrocytes, following trauma or disease, the expression of NF-κB-dependent genes is highly activated. We previously demonstrated that inactivation of astroglial NF-κB in vivo (GFAP-IκBα-dn mice) leads to improved functional outcome in experimental autoimmune encephalomyelitis (EAE), and this is accompanied by reduction of pro-inflammatory gene expression in the CNS. Here we extend our studies to show that recovery from EAE in GFAP-IκBα-dn mice is associated with reduction of peripheral immune cell infiltration into the CNS at the chronic phase of EAE. This is not dependent on a less permeable blood-brain barrier, but rather on a reduced immune cell mobilization from the periphery. Furthermore, once inside the CNS, the ability of T cells to produce pro-inflammatory cytokines is diminished during acute disease. In parallel, we found that the number of total and activated microglial cells is reduced, suggesting that functional improvement in GFAP-IκBα-dn mice is dependent upon reduction of the overall inflammatory response within the CNS sustained by both resident and infiltrating cells. This results in preservation of myelin compaction and enhanced remyelination, as shown by electron microscopy analysis of the spinal cord. Collectively our data indicate that astrocytes are key players in driving CNS inflammation and are directly implicated in the pathophysiology of EAE, since blocking their pro-inflammatory capability results in protection from the disease.

Linearized Bragg grating assisted electro-optic modulator.

We propose a new linearized electro-optic modulator in which linearization is achieved by modulating the index of a Bragg grating reflector placed in the arm(s) of a Michelson Interferometer. This grating-assisted Michelson (GAMI) modulator can operate as either an intensity or amplitude modulator, and is shown to significantly improve the linearity of microwave photonics links.

Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling.

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1(-/-) mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.

Catalyst Design for Rh-Catalyzed Arene and Alkane C-H Borylation: The NHC Affects the Induction Period, and Indenyl is Superior to Cp.

In order to establish design criteria for Rh C-H borylation catalysts, analogues of the successful catalyst [Rh(Ind)(SIDipp)(COE)] (Ind = η5-indenyl, SIDipp = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene, and COE = cis-cyclooctene) were synthesized by changing the indenyl and carbene ligands. [RhCp(SIDipp)(COE)] (1) formed alongside the C-C activated, cyclometalated byproduct [RhCp(κ2CAr,Ccarbene-SIDipp')(iPr)] (rac-2; SIDipp' = 1-(6-isopropylphenyl)-3-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene). Computational modeling of COE dissociation showed that both C-C and C-H activation of the SIDipp aryl group is thermally attainable and reversible under experimental conditions, with the C-C activation products being the more thermodynamically stable species. Oxidative addition of 1 with SiH(OEt)3 gave the Rh silyl hydride [RhCp(H){Si(OEt)3}(SIDipp)] (rac-3). [Rh(Ind)(IDipp)(COE)] (4; IDipp = 1,3-bis(2,6-diisopropylphenyl)-imidazole-2-ylidene), the carbonyl analogue [Rh(Ind)(IDipp)(CO)] (5; νCO = 1940 cm-1, cf. 1944 cm-1 for [Rh(Ind)(SIDipp)(COE)]), and [Rh(Ind)(IMe4)(COE)] (6; IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene) were also characterized, but attempts to synthesize Rh carbene complexes with fluorenyl or 1,2,3,4-tetrahydrofluorenyl ligands were not successful. For the catalytic C-H borylation of benzene using B2pin2, 1 was inactive at 80 °C, and [Rh(Ind)(SIDipp)(COE)] was superior to all other complexes tested due to the shortest induction period. However, the addition of HBpin to precatalyst 4 eliminated the induction period. Catalytic n-alkane C-H borylation using [Rh(Ind)(NHC)(COE)] gave yields of up to 21% alkylBpin, but [RhCp*(C2H4)2] was the better catalyst.

Reduced extracellular zinc levels facilitate glutamate-mediated oligodendrocyte death after trauma.

Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor-κB transcription factor in astrocytes reduces white matter damage and improves functional recovery following spinal cord injury. In the current study, we demonstrate that activation of the nuclear factor-κB transcription factor within astrocytes results in a significant increase in oligodendrocyte death following trauma by reducing extracellular zinc levels and inducing glutamate excitotoxicity. By using an ionotropic glutamate receptor antagonist (CNQX), we show that astroglial nuclear factor-κB-mediated oligodendrocyte death is dependent on glutamate signaling despite no change in extracellular glutamate concentrations. Further analysis demonstrated a reduction in levels of extracellular zinc in astrocyte cultures with functional nuclear factor-κB signaling following trauma. Cotreatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity under low-zinc conditions, suggesting that the presence of zinc at specific concentrations can prevent glutamate excitotoxicity. These studies demonstrate a novel role for zinc in regulating oligodendrocyte excitotoxicity and identify new therapeutic targets to prevent oligodendrocyte cell death in central nervous system trauma and disease.