Directly modulated deformed-square-FP coupled-cavity laser with intracavity-mode photon-photon resonance.

We propose and demonstrate a high-speed directly modulated laser based on a hybrid deformed-square-FP coupled cavity (DFC), aiming for a compact-size low-cost light source in next-generation optical communication systems. The deformed square microcavity is directly connected to the FP cavity and utilized as a wavelength-sensitive reflector with a comb-like and narrow-peak reflection spectrum for selecting the lasing mode, which can greatly improve the single-mode yield of the laser and the quality (Q) factor of the coupled mode. By optimizing the device design and operating condition, the modulation bandwidth of the DFC laser can be enhanced due to the intracavity-mode photon-photon resonance effect. Our experimental results show an enhancement of 3-dB modulation bandwidth from 19.3 GHz to 30 GHz and a clear eye diagram at a modulation rate of 25 Gbps.

Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Narrow linewidth optical frequency comb based on a directly modulated microcavity laser with optical feedback.

A narrow linewidth optical frequency comb (OFC) based on a directly modulated microcavity laser with external optical feedback is investigated numerically and demonstrated experimentally. Based on the numerical simulations with rate equations, the evolution of the optical and electrical spectra is presented for the direct-modulated microcavity laser with increased feedback strength, and the linewidth property is improved at suitable feedback conditions. The simulation results also show good robustness for the generated OFC in terms of feedback strength and phase. Moreover, the OFC generation experiment is performed by combining with the dual-loop feedback structure to suppress the side mode, and an OFC with a side-mode suppression ratio of 31 dB is realized. Thanks to the high electro-optical response of the microcavity laser, a 15-tone OFC with a frequency interval of 10 GHz is obtained. Finally, the linewidth of each comb tooth is measured to be around 7 kHz under the feedback power of 47 µW, which indicates an enormous compression of approximately 2000 times compared with the free-running continuous-wave microcavity laser.

Self-pulsing and dual-mode lasing in a square microcavity semiconductor laser.

Self-pulsing and dual-mode lasing in a square microcavity semiconductor laser are studied experimentally. Self-sustained pulses originating from undamped relaxation oscillation induced by a two-mode interaction are obtained, as the injection current is slightly above the laser threshold. A repetition frequency of 4.4 GHz and a pulse width of 30-40 ps are obtained at a current of 8 mA. The laser switches to continuous-wave operation when the injection current is higher than a certain value, and dual-mode lasing with 30.7 GHz at 16 mA and 10.7 GHz at 27 mA are observed in the lasing spectra. Furthermore, the relative intensity noise spectra are presented to reveal the relationship between the lasing states and the dynamics induced by relaxation oscillation and mode beating.

MiniCAFE, a CRISPR/Cas9-based compact and potent transcriptional activator, elicits gene expression in vivo.

CRISPR-mediated gene activation (CRISPRa) is a promising therapeutic gene editing strategy without inducing DNA double-strand breaks (DSBs). However, in vivo implementation of these CRISPRa systems remains a challenge. Here, we report a compact and robust miniCas9 activator (termed miniCAFE) for in vivo activation of endogenous target genes. The system relies on recruitment of an engineered minimal nuclease-null Cas9 from Campylobacter jejuni and potent transcriptional activators to a target locus by a single guide RNA. It enables robust gene activation in human cells even with a single DNA copy and is able to promote lifespan of Caenorhabditis elegans through activation of longevity-regulating genes. As proof-of-concept, delivered within an all-in-one adeno-associated virus (AAV), miniCAFE can activate Fgf21 expression in the liver and regulate energy metabolism in adult mice. Thus, miniCAFE holds great therapeutic potential against human diseases.

Nonlinear dynamics of a semiconductor microcavity laser subject to frequency comb injection.

The nonlinear dynamical behaviors of a semiconductor microcavity laser with frequency comb injection have been experimentally and numerically investigated. The microcavity laser is harmonically locked to a unit fraction of the comb spacing due to the undamped relaxation oscillation at certain conditions, creating additional comb lines with reduced frequency spacing. The stability maps indicating various locking states are obtained based on rate equations, which demonstrates that the locking regions are closely related to the relaxation oscillation. Moreover, the microcavity laser with comb injection leads to spectral broadening of the original comb and the number of comb lines raises from 3 to 13. Owing to the large modulation bandwidth of the microcavity laser, the comb lines and the frequency spacing can be tailored over a wide range by varying the injection parameters.

Manipulation of lasing modes in a circular-side octagonal microcavity laser with a spatially distributed current injection.

We propose and demonstrate a circular-side octagonal microcavity (COM) semiconductor laser with a spatially distributed current injection for manipulating the lasing modes. There are two types of high-quality-factor whispering-gallery (WG) modes with distinct field patterns in a COM: the four-bounced quadrilateral modes and the eight-bounced octagonal modes. By designing two separated p-electrodes, the COM laser is divided into two regions that are pumped independently to select specific modes for lasing. The two types of WG modes lase simultaneously when the two regions are injected with equivalent currents. Degeneracy removal of the quadrilateral modes is observed in both simulation and experiment when the two regions are injected with inequivalent currents. The quadrilateral modes are suppressed when one of the two regions is un-injected or biased with a negative current, and single-octagonal-mode lasing is realized. The results show that the lasing modes can be efficiently manipulated with the spatially distributed current injection considering the distinct field patterns of different WG modes in the microcavities, which can promote the practical application of the microcavity lasers.

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction.

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.

HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation.

Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis.