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.

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.

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.

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.

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.

Cross-Talk and Subset Control of Microglia and Associated Myeloid Cells in Neurological Disorders.

Neurological disorders are highly prevalent and often lead to chronic debilitating disease. Neuroinflammation is a major driver across the spectrum of disorders, and microglia are key mediators of this response, gaining wide acceptance as a druggable cell target. Moreover, clinical providers have limited ability to objectively quantify patient-specific changes in microglia status, which can be a predictor of illness and recovery. This necessitates the development of diagnostic biomarkers and imaging techniques to monitor microglia-mediated neuroinflammation in coordination with neurological outcomes. New insights into the polarization status of microglia have shed light on the regulation of disease progression and helped identify a modifiable target for therapeutics. Thus, the detection and monitoring of microglia activation through the inclusion of diagnostic biomarkers and imaging techniques will provide clinical tools to aid our understanding of the neurologic sequelae and improve long-term clinical care for patients. Recent achievements demonstrated by pre-clinical studies, using novel depletion and cell-targeted approaches as well as single-cell RNAseq, underscore the mechanistic players that coordinate microglial activation status and offer a future avenue for therapeutic intervention.

Neuroblast migration along cellular substrates in the developing porcine brain.

In the past decade it has become evident that neuroblasts continue to supply the human cortex with interneurons via unique migratory streams shortly following birth. Owing to the size of the human brain, these newborn neurons must migrate long distances through complex cellular landscapes to reach their final locations. This process is poorly understood, largely because of technical difficulties in acquiring and studying neurotypical postmortem human samples along with diverging developmental features of well-studied mouse models. We reasoned that migratory streams of neuroblasts utilize cellular substrates, such as blood vessels, to guide their trek from the subventricular zone to distant cortical targets. Here, we evaluate the association between young interneuronal migratory streams and their preferred cellular substrates in gyrencephalic piglets during the developmental equivalent of human birth, infancy, and toddlerhood.

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.

High-performance lasers for fully integrated silicon nitride photonics.

Silicon nitride (SiN) waveguides with ultra-low optical loss enable integrated photonic applications including low noise, narrow linewidth lasers, chip-scale nonlinear photonics, and microwave photonics. Lasers are key components to SiN photonic integrated circuits (PICs), but are difficult to fully integrate with low-index SiN waveguides due to their large mismatch with the high-index III-V gain materials. The recent demonstration of multilayer heterogeneous integration provides a practical solution and enabled the first-generation of lasers fully integrated with SiN waveguides. However, a laser with high device yield and high output power at telecommunication wavelengths, where photonics applications are clustered, is still missing, hindered by large mode transition loss, non-optimized cavity design, and a complicated fabrication process. Here, we report high-performance lasers on SiN with tens of milliwatts output power through the SiN waveguide and sub-kHz fundamental linewidth, addressing all the aforementioned issues. We also show Hertz-level fundamental linewidth lasers are achievable with the developed integration techniques. These lasers, together with high-Q SiN resonators, mark a milestone towards a fully integrated low-noise silicon nitride photonics platform. This laser should find potential applications in LIDAR, microwave photonics and coherent optical communications.

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.

Early Influences of Microbiota on White Matter Development in Germ-Free Piglets.

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans; however, the influence of microbiota on gyral WM development remains elusive. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life.

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.

Clearing techniques for visualizing the nervous system in development, injury, and disease.

Modern clearing techniques enable high resolution visualization and 3D reconstruction of cell populations and their structural details throughout large biological samples, including intact organs and even entire organisms. In the past decade, these methods have become more tractable and are now being utilized to provide unforeseen insights into the complexities of the nervous system. While several iterations of optical clearing techniques have been developed, some are more suitable for specific applications than others depending on the type of specimen under study. Here we review findings from select studies utilizing clearing methods to visualize the developing, injured, and diseased nervous system within numerous model systems and species. We note trends and imbalances in the types of research questions being addressed with clearing methods across these fields in neuroscience. In addition, we discuss restrictions in applying optical clearing methods for postmortem tissue from humans and large animals and emphasize the lack in continuity between studies of these species. We aim for this review to serve as a key outline of available tissue clearing methods used successfully to address issues across neuronal development, injury/repair, and aging/disease.

PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis.

PINK1 and Parkin are established mediators of mitophagy, the selective removal of damaged mitochondria by autophagy. PINK1 and Parkin have been proposed to act as tumor suppressors, as loss-of-function mutations are correlated with enhanced tumorigenesis. However, it is unclear how PINK1 and Parkin act in coordination during mitophagy to influence the cell cycle. Here we show that PINK1 and Parkin genetically interact with proteins involved in cell cycle regulation, and loss of PINK1 and Parkin accelerates cell growth. PINK1- and Parkin-mediated activation of TBK1 at the mitochondria during mitophagy leads to a block in mitosis due to the sequestration of TBK1 from its physiological role at centrosomes during mitosis. Our study supports a diverse role for the far-reaching, regulatory effects of mitochondrial quality control in cellular homeostasis and demonstrates that the PINK1/Parkin pathway genetically interacts with the cell cycle, providing a framework for understanding the molecular basis linking PINK1 and Parkin to mitosis.

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.

The operative treatment of shoulder pain in patients with a concurrent diagnosis of cervical spondylosis and shoulder dysfunction.

BACKGROUND: Etiology of neck and shoulder pain may be multifactorial. When surgical intervention is indicated, the choice of whether to start with spine or shoulder surgery is an important clinical decision to make based on severity of pathologies, comorbidities, and patient preference. The literature includes with very few studies exploring the incidence or results of the surgical treatment paths followed in this clinical situation. This study compares patient-reported outcomes of patients with both cervical spine and shoulder pathology who underwent intervention for cervical, shoulder, or both pathologies. METHODS: The authors retrospectively reviewed 154 charts at a single institution between 2009-2017 who had both cervical spine and shoulder pathology while undergoing operative intervention of one or both pathologies. For each patient, demographics, patient-perceived success, NRS pain scores, functional outcomes (Focus on Therapeutic Outcome scores and neck disability index scores), and post-operative opioid use were reported. RESULTS: Patient-reported success (P=0.85), NRS pain score decreases (P=0.45), all functional outcomes except for final external rotation range of motion (P=0.02), and post-operative opioid use (P=0.30) were similar when comparing only cervical spine to shoulder intervention. Success (P=1.00), NRS pain score decreases (P=0.37), both functional outcomes, and post-operative opioid use (P=0.08) were all similar when comparing patients who underwent cervical then shoulder intervention to shoulder then cervical intervention. Finally, statistical significance was found when comparing reported success (P=0.0004) but not NRS decreases (P=0.18), functional outcomes, or post-operative opioid use (P=0.43) in patients who underwent both operation types versus only one. CONCLUSIONS: Similar outcomes are seen when comparing isolated surgical intervention types and order of surgeries when undergoing both interventions. Multiple surgical intervention types, regardless of order, tends to result in higher rates of patient-reported success but similar post-operative outcomes compared to one.

Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease.

Background Reduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter. Methods and Results Transgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7-12). The proliferation (n=3-6), apoptosis (n=3-6), and developmental stage (n=5-8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia-induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3-4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6-10). Hypoxia worsened sensory-motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5-9). Conclusions Suboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.

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.

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.