Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses.

Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn2+ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn2+ was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn2+ enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn2+ also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.

Watt-level all polarization-maintaining femtosecond fiber laser source at 1100 †nm.

We demonstrate a compact watt-level all polarization-maintaining (PM) femtosecond fiber laser source at 1100 nm. The fiber laser source is seeded by an all PM fiber mode-locked laser employing a nonlinear amplifying loop mirror. The seed laser can generate stable pulses at a fundamental repetition rate of 40.71 MHz with a signal-to-noise rate of >100 dB and an integrated relative intensity noise of only ∼0.061%. After two-stage external amplification and pulse compression, an output power of ∼1.47 W (corresponding to a pulse energy of ∼36.1 nJ) and a pulse duration of ∼251 fs are obtained. The 1100 nm femtosecond fiber laser is then employed as the excitation light source for multicolor multi-photon fluorescence microscopy of Chinese hamster ovary (CHO) cells stably expressing red fluorescent proteins.

Low-noise mode-locking in a GHz repetition rate Tm3+-doped fiber laser.

We demonstrate a GHz repetition rate mode-locked Tm3+-doped fiber laser with low noise. Based on a home-made Tm3+-doped barium gallo-germanate fiber with reduced dispersion, a broad optical spectrum of mode-locking is achieved, and its amplified spontaneous emission quantum-limited timing jitter is largely suppressed. Besides, we carefully investigate the influence of the intracavity pump strength on the noise performance of the mode-locked pulses and find that manipulating the intracavity pump power can be an effective method for optimizing the timing jitter and relative intensity noise (RIN). Particularly, RIN, which originated from the relaxation oscillation, can be effectively suppressed by 33 dB at offset frequencies of >1 MHz. The integrated timing jitter and RIN are only 7.9 fs (10 kHz-10 MHz) and 0.05% (10 Hz-10 MHz), respectively.

Validation and depth evaluation of low-pass genome sequencing in prenatal diagnosis using 387 amniotic fluid samples.

BACKGROUND: Low-pass genome sequencing (LP GS) is an alternative to chromosomal microarray analysis (CMA). However, validations of LP GS as a prenatal diagnostic test for amniotic fluid are rare. Moreover, sequencing depth of LP GS in prenatal diagnosis has not been evaluated. OBJECTIVE: The diagnostic performance of LP GS was compared with CMA using 375 amniotic fluid samples. Then, sequencing depth was evaluated by downsampling. RESULTS: CMA and LP GS had the same diagnostic yield (8.3%, 31/375). LP GS showed all copy number variations (CNVs) detected by CMA and six additional variant of uncertain significance CNVs (>100 kb) in samples with negative CMA results; CNV size influenced LP GS detection sensitivity. CNV detection was greatly influenced by sequencing depth when the CNV size was small or the CNV was located in the azoospermia factor c (AZFc) region of the Y chromosome. Large CNVs were less affected by sequencing depth and more stably detected. There were 155 CNVs detected by LP GS with at least a 50% reciprocal overlap with CNVs detected by CMA. With 25 M uniquely aligned high-quality reads (UAHRs), the detection sensitivity for the 155 CNVs was 99.14%. LP GS using samples with 25 M UAHRs showed the same performance as LP GS using total UAHRs. Considering the detection sensitivity, cost and interpretation workload, 25 M UAHRs are optimal for detecting most aneuploidies and microdeletions/microduplications. CONCLUSION: LP GS is a promising, robust alternative to CMA in clinical settings. A total of 25 M UAHRs are sufficient for detecting aneuploidies and most microdeletions/microduplications.

Feature issue introduction: ultrafast optical imaging.

This feature issue of Optics Express collects 20 articles that report the most recent progress of ultrafast optical imaging. This review provides a summary of these articles that cover the spectrum of ultrafast optical imaging, from new technologies to applications.

Wideband ultra-low intensity noise reduction via joint action of gain saturation and out-of-phase polarization mixing effect from a semiconductor optical amplifier.

In this article, the vector dynamics of semiconductor optical amplifiers (SOAs) are systematically analyzed and developed to explore its mechanism of intensity noise suppression. First, theoretical investigation on the gain saturation effect and carrier dynamics is performed via a vectorial model, and the calculated result unravels desynchronized intensity fluctuations of two orthogonal polarization states. Particularly, it predicts an out-of-phase case, which allows the cancellation of the fluctuations via adding up the orthogonally-polarized components, then establishes a synthetic optical field with stable amplitude and dynamic polarization, and thereby enables a remarkable relative intensity noise (RIN) reduction. Here, we term this approach of RIN suppression as out-of-phase polarization mixing (OPM). To validate the OPM mechanism, we conduct an SOA-mediated noise-suppression experiment based on a reliable single-frequency fiber laser (SFFL) with the presence of relaxation oscillation peak, and subsequently carry out a polarization resolvable measurement. By this means, out-of-phase intensity oscillations with respect to the orthogonal polarization states are clearly demonstrated, and consequently enable a maximum suppression amplitude of >75 dB. Notably, the RIN of 1550-nm SFFL, suppressed by joint action of OPM and gain saturation effect, is dramatically reduced to -160 dB/Hz in a wideband of 0.5 MHz∼10 GHz, and the performance of which is excellent by comparing with the corresponding shot noise limit of -161.9 dB/Hz. The proposal of OPM here not only facilitates us to dissect the vector dynamics of SOA but also offers a promising solution to realize wideband near-shot-noise-limited SFFL.

1200-W all polarization-maintaining fiber GHz-femtosecond-pulse laser with good beam quality.

In this work, we demonstrate a 1200-W average power all polarization-maintaining (PM) fiber ultrafast laser system operating at 1.0 µm. In accordance with the numerical modeling, the PM fiber laser system is designed and it delivers linearly-polarized femtosecond pulses at a 1.39-GHz fundamental repetition rate, with a maximum output power of 1214 W - to the best of our knowledge, the highest average power from all PM fiber ultrafast laser at 1.0 µm to date. The pulse width can be compressed to ∼800 fs with a beam quality of M2 < 1.1. This kilowatt-class all PM fiber laser system is expected to open new potential for high energy pulse generation through temporal coherent combination and laser ablation using GHz burst fs laser.

Ultrafine electro-optical frequency comb based on cascade phase modulation with cyclic frequency shifting.

An ultrafine electro-optical frequency comb (EOFC) with plentiful comb teeth is demonstrated. Adopting a single-frequency fiber laser as a light source, cascade phase modulation based on a sinusoidal signal and a frequency-time transformation (FTT) signal is executed to generate the EOFC with high fineness. Meanwhile, a cyclic fast frequency shifting strategy is introduced to boost the number of comb teeth and the bandwidth of the EOFC. As a result, an EOFC with 12600 comb lines covering a broad bandwidth from -6.3 GHz to 6.3 GHz is established, corresponding to an ultrafine comb space of 1 MHz. Moreover, the power fluctuation of a comb tooth is less than 0.5 dBm. This state-of-the-art EOFC has significant potential in the field of precision spectroscopy.

Threshold reduction of GHz-repetition-rate passive mode-locking by tapering the gain fiber.

Passively mode-locked fiber lasers with GHz repetition rates have recently attracted significant attention in frontier research areas, including frequency-comb spectroscopy, coherent optical communication, photonic radar, micromachining, etc. In general, the threshold of passive mode-locking increases with the fundamental repetition rate, which is inversely proportional to the cavity length, and this sets a limit on the scalability of the fundamental repetition rate. To overcome this issue, here we propose to reduce the threshold of continuous-wave mode-locking (CWML) by precisely tapering the gain fiber, which can enhance the power density incident on the semiconductor saturable absorber mirror. Assisted by the analysis of guiding property, an experimental scheme is established for tapering standard Yb-doped fibers (125 µm cladding diameter), and tapered Yb-doped fibers with different waist diameters can be fabricated. Using a tapered Yb-doped gain fiber with waist cladding diameter of 90 µm, we are able to achieve CWML with a fundamental repetition rate of 3.3 GHz, and reduce its mode-locking threshold by 31%. More importantly, the optical spectrum of the CWML is found to be broadened with the waist diameter reduction of the gain fiber, which is beneficial for generating shorter transform-limited pulses. The efforts made in this work can provide a promising route to realize stable high-repetition-rate mode-locked fiber lasers with moderate levels of pump power.

Ultrafast fiber laser at 0.9 µm with a gigahertz fundamental repetition rate by a high gain Nd3+-doped phosphate glass fiber.

Fiber lasers, owing to the advantages of excellent beam quality and unique robustness, play a crucial role in lots of fields in modern society. Developing optical glass fibers with superior performance is of fundamental importance for wide applications of fiber lasers. Here, a new Nd3+-doped phosphate single-mode fiber that enables a high gain at 0.9 µm is designed and fabricated. Compared to previous Nd3+-doped silica fibers, the developed phosphate fiber exhibits a significant gain promotion, up to 2.7 dB cm-1 at 915 nm. Configuring in a continuous-wave fiber laser, this phosphate fiber can provide a slope efficiency of 11.2% in a length of only 4.5 cm, about 6 times higher than that of Nd3+-doped silica fiber. To showcase its uniqueness, an ultrafast fiber laser with ultrashort cavity is constructed, such that an ultrashort pulse train with a fundamental repetition rate of up to 1.2 GHz is successfully generated. To the best of our knowledge, this is the highest fundamental repetition rate for mode-locked fiber lasers at this wavelength range - two orders of magnitude higher than that of prior works. These results indicate that this Nd3+-doped phosphate fiber is an effective gain medium for fiber amplifiers and lasers at 0.9 µm, and it is promising for two-photon biophotonics that requires long-term operation with low phototoxicity.

Broadband high-gain Tm3+/Ho3+ co-doped germanate glass multimaterial fiber for fiber lasers above 2 µm.

High-gain Tm3+/Ho3+ co-doped optical fibers are urgently desired for high-repetition-rate mode-locked fiber lasers at >2 µm. Here, Tm3+/Ho3+ co-doped germanate glass with low hydroxyl (OH-) content was prepared by the conventional melt-quenching method combined with the reaction atmosphere procedure (RAP) dehydration technique. The doping concentrations of Tm2O3 and Ho2O3 are 2.5 mol.% (7.1 wt.%) and 0.25 mol.% (0.7 wt.%), respectively. Thanks to the high Tm3+ doping (7.1 wt.%) and low energy transfer efficiency (19.8%) between Tm3+ and Ho3+ ions, it enables achieving broadband and high-gain performance in the 2 µm region. Then a silicate-clad Tm3+/Ho3+ co-doped germanate core multimaterial fiber was successfully drawn by using the rod-in-tube method, which has a broadband amplified spontaneous emission (ASE) with a full width at half-maximum (FWHM) of 247.8 nm at 2 µm. What is more, this new fiber has a high gain per unit length of 4.52 dB/cm at 1.95 µm. Finally, an all-fiber-integrated passively mode-locked fiber laser was built by using this broadband high-gain fiber. The mode-locked pulses operate at 2068.05 nm, and the fundamental repetition rate is up to 4.329 GHz. To the best of our knowledge, this is the highest fundamental repetition rate for the all-fiber passively mode-locked fiber laser above 2 µm. These results suggest that the as-drawn multimaterial fibers with broadband high-gain characteristics are promising for high-repetition-rate ultrafast fiber lasers.

Manipulating the polarization dynamics in a >10-GHz Er3+/Yb3+ fiber Fabry-Pérot laser.

In this work, we report on the vector and scalar soliton dynamics that result from inevitable fiber birefringence in an 8-mm Er3+/Yb3+ fiber based Fabry-Férot (FP) laser that has a free spectral range of up to 12.5 GHz. The generation of polarization-evolving vector solitons can largely degrade the performance of application systems, and the underlying mechanisms and manipulation technologies are yet to be explored. To realize the transition from vector to scalar (linearly polarized) state, we here incorporate the polarization selection effect (PSE) in the simulation model and the numerical results verify that only a small amount of PSE is sufficient for manipulating the soliton dynamics. It also reveals that, prominent polarization-dependent intensity discrimination can be acquired via geometry-induced oblique incidence to the Bragg mirror of the semiconductor saturable absorber mirror (SESAM), and we obtain switchable operating states by tilting the SESAM in the experiments. These efforts create a feasible method to manipulate high-repetition-rate pulse and may shed light on understanding the dissipative soliton dynamics in ultrafast fiber FP lasers.

High-speed wavelength-swept femtosecond source from 1055 to 1300†nm using a GHz femtosecond fiber laser.

In this Letter, we demonstrate a high-speed broadband wavelength-swept femtosecond source (WFS) that leverages the soliton self-frequency shift (SSFS) and intensity-wavelength encoding technologies. The optical wavelength of the high-speed WFS can be continuously swept from 1055 nm to nearly 1300 nm at a sweeping rate of 100 kHz. This WFS is especially seeded by a femtosecond mode-locked all-fiber laser at 1055 nm that has a fundamental repetition rate of ∼1.0 GHz, a maximum output power of 7 W, and a compressed pulse width of 220 fs. It is anticipated that this high-speed broadband WFS can be a promising source for applications that require fast wavelength scanning and high-speed data processing.

>10†GHz femtosecond fiber laser system at 2.0†µm.

We demonstrate a high-power 2.0-µm fiber laser system delivering femtosecond pulses with a fundamental repetition rate of >10 GHz, the highest value so far, to the best of our knowledge. The seed is a self-started fundamentally mode-locked Tm-doped fiber laser that has excellent power and spectral stabilities. The laser system can provide an average power of >600 mW, and the use of soliton-effect-based pulse compression allows the achievement of a pulse duration of 163 fs, leading to a compression factor of ∼ 13. It is anticipated that this new high-power femtosecond fiber laser with a 10-GHz-level fundamental repetition rate can serve as a promising light source for various applications, including laser surgery, micromachining, frequency comb spectroscopy, and nonlinear frequency conversion.

Watt-level gigahertz femtosecond fiber laser system at 920 nm.

We demonstrate a watt-level femtosecond fiber laser system at 0.9 µm with a repetition rate of >1 GHz, which is the highest value reported so far for a fundamental mode-locked fiber laser. The fiber laser system is seeded by a fundamental mode-locked fiber laser constructed with a home-made highly Nd3+-doped fiber. After external amplification and pulse compression, an output power of 1.75 W and a pulse duration of 309 fs are obtained. This compact fiber laser system is expected to be a promising laser source for biological applications, particularly two-photon excitation microscopy.

4.3†GHz fundamental repetition rate passively mode-locked fiber laser using a silicate-clad heavily Tm3+-doped germanate core multimaterial fiber.

We report a silicate-clad heavily Tm3+-doped germanate core multimaterial fiber that is successfully drawn by using a rod-in-tube method. This new fiber has a high gain per unit length of 6.11 dB/cm at 1.95 µm, which is, to the best of the authors' knowledge, the highest gain per unit length reported so far for Tm3+-doped glass fibers. By virtue of this high-gain glass fiber, an all-fiber-integrated passively mode-locked fiber laser with a fundamental repetition rate up to 4.3 GHz is demonstrated. Remarkably, the generated pulse operating at 1968 nm exhibits a signal-to-noise ratio of >76 dB in the radio-frequency domain. These results suggest that the silicate-clad heavily Tm3+-doped germanate core multimaterial fiber can act as a key building block for high repetition rate mode-locked fiber lasers at 2 µm.

All-fiber mode-locked gigahertz femtosecond laser at 1610 nm using a self-developed long-wavelength gain fiber.

We report a compact all-fiber passively mode-locked ultrafast laser with a fundamental repetition rate of 1.6 GHz that uses a self-developed long-wavelength active fiber, i.e., a fluoro-sulfo-phosphate-based Er3+/Yb3+ co-doped fiber (only 6.2 cm in length). This active fiber can provide a net gain coefficient of 0.6 dB/cm at 1610 nm. The high-repetition-rate all-fiber mode-locked laser operates at a low pump power of only approximately 90 mW. The mode-locked pulse train has a period of 625 ps and a 3 dB bandwidth of 7.0 nm, which can support a transform-limited pulse width of 390 fs.

[A consensus on prenatal diagnosis and genetic counseling for chromosomal mosaicism].

With the extensive application of highly sensitive genetic techniques in the field of prenatal diagnosis, prenatal chromosomal mosaicisms including true fetal mosaicisms and confined placental mosaicisms are frequently identified in clinical settings, and the diagnostic criteria and principle of genetic counseling and clinical management for such cases may vary significantly among healthcare centers across the country. This not only has brought challenges to laboratory technician, genetic counselor and fetal medicine doctor, but can also cause confusion and anxiety of the pregnant woman and their family members. In this regard, we have formulated a consensus over the prenatal diagnosis and genetic counseling for chromosomal mosaicisms with the aim to promote more accurate and rational evaluation for fetal chromosomal mosaicisms in prenatal clinics.

AutoCNV: a semiautomatic CNV interpretation system based on the 2019 ACMG/ClinGen Technical Standards for CNVs.

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) presented technical standards for interpretation and reporting of constitutional copy-number variants in 2019 (the standards). Although ClinGen developed a web-based CNV classification calculator based on scoring metrics, it can only track and tally points that have been assigned based on observed evidence. Here, we developed AutoCNV (a semiautomatic automated CNV interpretation system) based on the standards, which can automatically generate predictions on 18 and 16 criteria for copy number loss and gain, respectively. RESULTS: We assessed the performance of AutoCNV using 72 CNVs evaluated by external independent reviewers and 20 illustrative case examples. Using AutoCNV, it showed that 100 % (72/72) and 95 % (19/20) of CNVs were consistent with the reviewers' and ClinGen-verified classifications, respectively. AutoCNV only required an average of less than 5 milliseconds to obtain the result for one CNV with automated scoring. We also applied AutoCNV for the interpretation of CNVs from the ClinVar database and the dbVar database. We also developed a web-based version of AutoCNV (wAutoCNV). CONCLUSIONS: AutoCNV may serve to assist users in conducting in-depth CNV interpretation, to accelerate and facilitate the interpretation process of CNVs and to improve the consistency and reliability of CNV interpretation.

Biocompatible diameter-oscillating fiber with microlens endface.

Optical fibers have been widely applied to life science, such as laser delivering, fluorescence collection, biosensing, bioimaging, etc. To resolve the challenges of advanced multiphoton biophotonic applications utilizing ultrashort laser pulses, here we report a flexible diameter-oscillating fiber (DOF) with microlens endface fabricated by using Polydimethylsiloxane (PDMS) elastomers. The diameter of the DOF is designed to longitudinally vary for providing accurate dispersion management, which is important for near-infrared multiphoton biophotonics that usually involves ultrashort laser pulses. The variation range and period of the DOF's diameter can be flexibly adjusted by controlling the parameters during the fabrication, such that dispersion curves with different oscillation landscapes can be obtained. The dispersion oscillating around the zero-dispersion baseline gives rise to a minimized net dispersion as the ultrashort laser pulse passes through the DOF - reducing the temporal broadening effect and resulting in transform-limited pulsewidth. In addition, the endface of the DOF is fabricated with a microlens, which is especially useful for laser scanning/focusing and fluorescence excitation. It is anticipated that this new biocompatible DOF is of great interest for biophotonic applications, particularly multiphoton microscopy deep inside biological tissues.