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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. US National Institutes of Health [R15NS108183] Published version ACKNOWLEDGMENTS We gratefully thank Drs. Sherrie Clark-Deener and Calvin Lau for their assistance with veterinary services. We are also thankful to Jessica Neary and Garrett Walker for assistance in animal husband-ry. We also would like to thank Raymundo Hernandez, Beatriz Torres, Swagatika Paul, and Dr. Alicia Pickrell for technical advice. We would like to acknowledge Karen Hall and Rachel McNeil for animal care. This work was supported by the US National Institutes of Health (R15NS108183 to P.D.M.) .

This paper describes the design, fabrication, and record performance of a new class of ultra-wideband wavelength tuning, ultra-low noise semiconductor laser, the Integrated Coherent Tunable Laser (ICTL). The ICTL device is designed for, and fabricated in, a CMOS foundry based Silicon Photonics platform, utilizing heterogeneous integration of III-V material to create the integrated gain section of the laser - enabling high-volume mass-market manufacturing at low cost and with high reliability. The ICTL incorporates three or more ultra-low loss micro-ring resonators, with large ring size, in a Sagnac loop reflector geometry, creating exceptional laser reflector performance, plus an extended laser cavity length that enables highly-coherent output; ultra-low linewidth and phase noise. This paper describes record integrated laser performance; 118 nm wavelength tuning, covering S-, C- and L-bands, with Lorentzian linewidth

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 vivousing chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes arein vivoactive 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 discoveredN-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3)in vivothrough 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 showedScrn3male 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.

Carbon-hydrogen bond activations and their subsequent functionalisation have long been an important target in chemistry because C-H bonds are ubiquitous throughout nature, making C-H derivatisation reactions highly desirable. The selective and efficient functionalisation of this bond into many more useful carbon-element bonds (e.g., C-B, C-Si, C-O, and C-S bonds) would have many uses in pharmaceutical and bulk chemical synthesis. Activation of the C-H bond is, however, challenging due to the high strength and low bond-polarity of this bond rendering its cleavage unfavourable. With the correct choice of reagents and systems, especially those utilising directing groups, kinetically and thermodynamically favourable catalytic processes have been developed. However, a key remaining challenge is the development of undirected, intermolecular reactions using catalysts that are both selective and active enough to make useful processes. In this review, the progress towards optimising group 9 C-H activation catalysts is discussed, particularly focusing on undirected reactions that are kinetically more difficult, starting with a brief history of C-H activation, identifying the importance of auxiliary ligands including the nature of anionic ligand (e.g., cyclopentadienyl, indenyl, fluorenyl, trispyrazolylborate) and neutral ligands (e.g., phosphines, carbonyl, alkenes, N-heterocyclic carbenes) that contribute towards the stability and reactivity of these metal complexes. The tethering of the anionic ligand to strong σ-donating ligands is also briefly discussed. The focus of this review is primarily on the group 9 metals rhodium and iridium, however, C-H activation using group 8 and 10 metals are compared where useful. The most recent advances in this field include the development of C-H borylation of many small hydrocarbon substrates such as arenes, heterocycles and n-alkanes as well as the more challenging substrate methane.

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., Achieving high output power and low noise integrated lasers is a major challenge. Here the authors experimentally demonstrate integrated lasers from a Si/SiN heterogeneous platform that shows Hertz-level linewidth, paving the way toward fully integrating low-noise silicon nitride photonics in volume using real devices for lasing.

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. Published version

Precision optical-frequency and phase synchronization over fibre is critical for a variety of applications, from timekeeping to quantum optics. Such applications utilize ultra-coherent sources based on stabilized table-top laser systems. Chip-scale versions of these systems may dramatically broaden the application landscape by reducing the cost, size and power of such exquisite sources. Links based on the required narrow-linewidth integrated lasers, compact reference cavities and control methodologies have not yet been presented. Here, we demonstrate an optically synchronized link that achieves an ultralow residual phase error variance of 3 × 10−4 rad2 at the receiver, using chip-scale stabilized lasers with laser linewidth of ~30 Hz and instability below 2 × 10−13 at 50 ms. This performance is made possible with integrated Brillouin lasers, compact reference cavities and a novel low-bandwidth optical-frequency-stabilized phase-locked loop. These results demonstrate a path towards low-power, precision applications including distributed atomic clocks, quantum links, database synchronization and digital-signal-processor-free coherent fibre interconnects. An optically synchronized precision fibre link based on two independent chip-scale cavity-stabilized stimulated Brillouin scattering lasers is demonstrated. An ultralow 3 × 10−4 rad2 residual phase error variance is achieved between the mutually coherent transmit and receive lasers.

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.

The continued growth in Hyperscale data center (HDC) deployment is expected to drive world-wide Internet traffic to an astounding 21 zettabytes by 2021. This growth will place increased demands on data center interconnects (DCIs) and drive the capacity of the underlying electronic application specific integrated circuit (ASIC) switch chips that route DCI ethernet traffic, from 12.8 Tbps per chip today to 100 Tbps and beyond in the future. This astounding growth will push the limits of today's incoherent fiber link technologies that connect switches, including power dissipation, density, and practical engineering solutions. To overcome these limits, high capacity coherent WDM, traditionally relegated to the metro and long-haul networks, will need to move into the DCI. However, migrating coherent WDM into the DCI, particularly for link distances less than 2 km, will require elimination of power consuming and costly technologies like the digital signal processor (DSP). Additionally, new photonic integration technologies will be needed to co-locate the coherent optical interfaces directly with switch ASICs to alleviate the bandwidth, power, and density limits. In this article, we introduce a new approach to DSP-free coherent WDM for the DCI called FRESCO: FREquency Stabilized Coherent Optical Links for Low Energy DCIs. FRESCO utilizes spectrally pure, ultra-stable light source technology, normally associated with high-end scientific applications like atomic clocks, to enable high capacity high-order WDM QAM with low bandwidth, low power electronics normally associated with RF links. Terabits per second FRESCO links based on shared, stabilized sources and high-density coherent WDM silicon photonic coherent transceivers that are co-located with the switch ASIC will pave the way to a DSP-free coherent WDM scalable DCI solution.

This paper presents recent results on widely-tunable narrow-linewidth semiconductor lasers using a ring-resonator based mirror as the extended cavity. Two generations of lasers on the heterogeneous Si/InP photonic platform are presented. The first-generation lasers, with a total footprint smaller than 0.81 mm2, showed an intrinsic linewidth of ∼2 kHz over a 40 nm wavelength tuning range across C+L bands. The second-generation lasers using ultra-low loss silicon waveguides and a novel cavity design achieved an intrinsic linewidth below 220 Hz. The lasers also possess an ultrawide wavelength tuning range of 110 nm across three optical communication bands (S+C+L). These are records among all fully integrated semiconductor lasers reported in the literature.

This invited paper reviews work towards creating ultra-low noise semiconductor laser sources with performance exceeding solid-state and fiber lasers, together with progress in the development of CMOS foundry Silicon Photonics versions of these devices.

Deprotonation of the fluorenyl-tethered imidazolinium salt [9-(C13H9)C2H4N(CH)C2H4N(2,4,6-Me3C6H2)][BF4] gave a spirocyclic compound that reacted with a synergic mixture of LiPh/LiN(SiMe3)2 or LinBu/LiN(SiMe3)2 to give a dilithium complex incorporating a bridging N(SiMe3)2 ligand. In contrast, deprotonation of the imidazolium salt [9-(C13H9)C2H4N(CH)C2H2N(Me)][Br] instead yielded the free NHC, which reacted with nBuLi to form a dimeric, NHC-bridged dilithium complex. Addition of LiN(SiMe3)2 led to coordination and the formation of a dilithium complex with a bridging N(SiMe3)2 ligand, which was characterised in the solid state as a 1D coordination polymer. The reaction of 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) with lithium indenide and lithium fluorenide gave soluble species with terminal binding of the NHC to the lithium cation and η5 coordination of indenyl or fluorenyl. A symmetrical bridging mode for an NHC donor was therefore observed only if a tethered fluorenyl anion was present with no additional amide ligand.

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.

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.

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. Due 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 due to 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.

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.

Optical isolators and circulators are fundamental building block in photonic integrated circuits to block undesired reflections and routing light according to a prescribed direction. In silicon photonics, heterogeneous integration of magneto-optic garnet bonded on a pre-patterned silicon layer has been demonstrated to be an effective solution for manufacturing optical isolators and circulators for TM polarized light. However, most integrated semiconductor lasers emit TE polarized light, which indicates the need to find a reliable solution for this polarization. In this paper, we demonstrated broadband optical isolators and circulators for TE polarized light based on heterogeneous bonding on the silicon photonics platform. To achieve this goal, an integrated adiabatic coupler and a broadband polarization rotator are designed and optimized. The nonreciprocal behavior is induced through an energy-efficient integrated electromagnet with a minimum power consumption of 3 mW. Two isolators/circulators are fabricated with small and large free spectral range, respectively. In the former case, an optical isolation ratio as large as 30 dB is measured at 1555 nm with an insertion loss of 18 dB, while for the broadband circulator, an optical isolation larger than 15 dB is guaranteed over more than 14 nm (1.75 THz) for all port combinations with an insertion loss between 14 and 18 dB at 1560 nm. Finally, it has been theoretically shown that the insertion loss can be reduced below 6 dB with design and fabrication improvements. To the best of the authors’ knowledge, the proposed integrated TE optical circulator is the first experimental demonstration of this device in silicon photonics.

Laser stabilization sits at the heart of many precision scientific experiments and applications, including quantum information science, metrology and atomic timekeeping. These systems narrow the laser linewidth and stabilize the carrier by use of Pound-Drever-Hall (PDH) locking to a table-scale, ultra-high quality factor (Q), vacuum spaced Fabry-Perot reference cavity. Integrating these cavities, to bring characteristics of PDH stabilization to the chip-scale, is critical to reduce their size, cost, and weight, and enable a wide range of portable and system-on-chip applications. We report a significant advance in integrated laser linewidth narrowing, stabilization and noise reduction, by use of a photonic integrated 4.0-meter-long coil resonator to stabilize a semiconductor laser. We achieve a 36 Hz 1/{\pi}-integral linewidth, an Allan deviation (ADEV) of 1.8x10^{-13} at 10 ms measurement time, and a 2.3 kHz/sec drift, to the best of our knowledge the lowest integral linewidth and highest stability demonstrated for an integrated reference cavity. Two coil designs, stabilizing lasers operating at 1550 nm and 1319 nm are demonstrated. The resonator is bus coupled to a 4.0-meter-long coil, with a 49 MHz free spectral range (FSR), a mode volume of 1.0x10^{10} {\mu}m^3 and a 142 million intrinsic Q, fabricated in a CMOS compatible, ultra-low loss silicon nitride waveguide platform. Our measurements and simulations show that the thermorefractive noise floor for this particular cavity is reached for frequencies down to 20 Hz in an ambient environment with simple passive vibration isolation and without vacuum or thermal isolation. The TRN limited performance is estimated to be an 8 Hz 1/{\pi} integral linewidth and ADEV of 5x10^{-14} at 10 ms, opening a stability regime that heretofore has only been available in fundamentally un-integrated systems., Comment: arXiv admin note: text overlap with arXiv:2107.03595

Silicon Photonics foundry based Integrated Coherent Tunable Laser (ICTL) devices display record performance; 118 nm wavelength tuning covering S-, C- and L-bands, Lorentzian linewidths below 100 Hz, and –155 dBc/Hz relative intensity noise.

We report an ultra-high Q Si3N4 waveguide resonator Brillouin laser stabilized to an identical waveguide resonator to achieve a linewidth of 292 Hz and a record high stability of 6.5 × 10–13 at 8 ms.

Silicon Photonics foundry based Extended-Distributed Bragg Reflector (E-DBR) lasers for automotive FMCW LiDAR systems are described, demonstrating record Lorentzian linewidths

Silicon nitride has excellent properties for photonic integrated circuits, where integration of lasers makes many new devices possible. Here we show recent progress of high performance heterogeneously integrated lasers using silicon nitride waveguides.

We report laser stabilization with record low frequency noise of 0.08 Hz2/Hz at 70 kHz offset and a 150 Hz integral linewidth using an integrated 4-meter waveguide coil resonator with 144 Million intrinsic Q.

Known chemoproteomic probes generally use warheads that tag a single type of amino acid or modified form thereof to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electron-poor enzyme cofactors, transient intermediates and chemically-labile regulatory modifications, but probes for such species are underdeveloped. Here, we have innovated a versatile class of chemoproteomic probes for this less charted hemisphere of the proteome by using hydrazine as the common chemical warhead. Its electron-rich nature allows it to react by both polar and radicaloid mechanisms and to target multiple, pharmacologically important functional classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment can be blocked by active-site-directed inhibitors, and elaboration of the warhead supports connection of a target to a lead compound. The capacity of substituted hydrazines to profile, discover and inhibit diverse cofactor-dependent enzymes enables cell and tissue imaging and makes this platform useful for enzyme and drug discovery.

We demonstrate the first heterogeneously integrated laser with a Si3N4 external cavity. Through a multilayer heterogeneous integration with InP and Si, the laser shows narrow linewidth and high temperature stability expected from a Si3N4 cavity.

We demonstrate a chip-scale ultra-narrow-linewidth stimulated Brillouin scattering laser pumped by a narrow-linewidth, tunable silicon/III-V laser. Reduction of ~600x in fundamental linewidth (1.1kHz to 1.8Hz) and ~9x in integral linewidth (110kHz to 12kHz) is achieved.

We demonstrate a DSP-free 16-QAM/50GBd link based on independent transmit and LO frequency-stabilized ultra-narrow-linewidth SBS lasers, with ~40Hz integral linewidths and 7x10-14 fractional frequency stability. The low-BW optical-frequency-stabilized-PLL with 3×10-4 rad2 phase error operates within 1% of DSP and self-homodyne.

This paper describes the design, fabrication, and excellent performance achieved with prototype hybrid lasers incorporating a high performance gain chip coupled into a fiber external cavity including a novel fiber Bragg grating (FBG) reflector. Packaged ultra-low noise (ULN) hybrid lasers operating at 1550 nm and at 1319 nm with high output power, >100 mW, and extremely low relative intensity noise (RIN) are described. Devices provide extremely stable singlemode output with high side-mode suppression ratio (SMSR), typically above 70 dB, with worst case measured RIN at microwave frequencies (1–20 GHz) being below –165 dBc/Hz. Operation of these high power, low RIN devices within an analog optical link demonstrates a Spurious Free Dynamic Range as high as 114.6 dB.Hz 2/3. In addition to high power and very low RIN, the ULN hybrid lasers provide extremely small low frequency phase noise, with Lorentzian linewidths down to 15 Hz, enabling key Microwave Photonics and Optical Sensing applications. A comparison of the phase noise and Lorentzian linewidth of ULN lasers with different FBG designs / external cavity lengths is described, demonstrating the novel hybrid approach for achieving extremely low phase noise lasers.

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 STATEMENTAlthough 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.

Optical circulators that unidirectionally route light could lead to bidirectional operations in applications in data centers and telecommunications, as well as sensors. In this work, to the best of our knowledge, we present the first realization of integrated optical circulators on silicon that are electrically driven and dynamically reconfigurable. The proposed device utilizes silicon microrings with a bonded magneto-optic cladding alongside an integrated electromagnet for nonreciprocal behavior. This novel approach does not use a permanent magnet and, for this reason, it is more attractive for packaging and further integration with lasers and other photonic devices. We use this device architecture to demonstrate 4- and 6-port optical circulators with up to 14.4 dB of isolation and propose a framework to extend the design to an arbitrary number of ports. Finally, we demonstrate that it is possible to switch the electromagnet and reconfigure the circulator on a sub-nanosecond timescale, potentially adding a new level of device functionality.

We observed that the transient induction of mtDNA double strand breaks (DSBs) in cultured cells led to activation of cell cycle arrest proteins (p21/p53 pathway) and decreased cell growth, mediated through reactive oxygen species (ROS). To investigate this process in vivo we developed a mouse model where we could transiently induce mtDNA DSBs ubiquitously. This transient mtDNA damage in mice caused an accelerated aging phenotype, preferentially affecting proliferating tissues. One of the earliest phenotypes was accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking age-related thymic involution. This phenotype was accompanied by increased ROS and activation of cell cycle arrest proteins. Treatment with antioxidants improved the phenotype but the knocking out of p21 or p53 did not. Our results demonstrate that transient mtDNA DSBs can accelerate aging of certain tissues by increasing ROS. Surprisingly, this mtDNA DSB-associated senescence phenotype does not require p21/p53, even if this pathway is activated in the process.

We present a widely tunable all-optical local oscillator (LO) scheme using two ultra-low noise, single cavity stabilized semiconductor lasers. Our all-optical LO with low phase noise and wide 4–32 GHz tuning range is readily extendable beyond 100 GHz for flexible optical down-conversion of RF signals.