Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

Chemogenetic approaches reveal dual functions of microglia in seizures.

Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia using the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that acute Gi-Dreadd activation with Clozapine-N-Oxide can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses of CNO over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon ß signaling and microglia proliferation. Thus, our findings highlight the importance of microglial Gi signaling not only during status epilepticus (SE) but also within later seizure induced pathology.

Ldl-stimulated microglial activation exacerbates ischemic white matter damage.

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

Exosomal lncRNA HEIH, an essential communicator for hepatocellular carcinoma cells and macrophage M2 polarization through the miR-98-5p/STAT3 axis.

Part of human long noncoding RNAs (lncRNAs) has been elucidated to play an essential role in the carcinogenesis and progression of hepatocellular carcinoma (HCC), a type of malignant tumor with poor outcomes. Tumor-derived exosomes harboring lncRNAs have also been implicated as crucial mediators to orchestrate biological functions among neighbor tumor cells. The recruitment of tumor-associated macrophages (TAMs) exerting M2-like phenotype usually indicates the poor prognosis. Yet, the precise involvement of tumor-derived lncRNAs in cross-talk with environmental macrophages has not been fully identified. In this study, we reported the aberrantly overexpressed HCC upregulated EZH2-associated lncRNA (HEIH) in tumor tissues and cell lines was positively correlated with poor prognosis, as well as enriched exosomal HEIH levels in blood plasma and cell supernatants. Besides, HCC cell-derived exosomes transported HEIH into macrophages for triggering macrophage M2 polarization, thereby in turn promoting the proliferation, migration, and invasion of HCC cells. Mechanistically, HEIH acted as a miRNA sponge for miR-98-5p to up-regulate STAT3, which was then further verified in the tumor xenograft models. Collectively, our study provides the evidence for recognizing tumor-derived exosomal lncRNA HEIH as a novel regulatory function through targeting miR-98-5p/STAT3 axis in environmental macrophages, which may shed light on the complicated tumor microenvironment among tumor and immune cells for HCC treatment.

Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers.

Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment option for RCC due to the lack of significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used to treat gastrointestinal tumors and renal cell carcinoma, inhibits the tyrosine kinase activity of a number of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, rearranged during transfection (RET) and fms-related receptor tyrosine kinase 3 (Flt3). Although sunitinib has been shown to be efficacious in the treatment of patients with advanced RCC, a significant number of patients have primary resistance to sunitinib or acquired drug resistance within the 6-15 months of therapy. Thus, in order to develop more efficacious and long-lasting treatment strategies for patients with advanced RCC, it will be crucial to ascertain how to overcome sunitinib resistance that is produced by various drug resistance mechanisms. In this review, we discuss: 1) molecular mechanisms of sunitinib resistance; 2) strategies to overcome sunitinib resistance and 3) potential predictive biomarkers of sunitinib resistance.

Trem2 deficiency attenuates microglial phagocytosis and autophagic-lysosomal activation in white matter hypoperfusion.

Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.

TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination.

Wavelength-versatile deep-red laser source by intracavity frequency converted Raman laser.

We demonstrate an efficient wavelength-selectable output in the attractive deep-red spectral region from an intracavity frequency converted Nd:YLF/KGW Raman laser. Driven by an acousto-optic Q-switched 1314 nm Nd:YLF laser, two first-Stokes waves at 1461 and 1490 nm were generated owing to the bi-axial properties of KGW crystal. By incorporating intracavity sum-frequency generation and second-harmonic generation with an angle-tuned bismuth borate (BIBO) crystal, four discrete deep-red laser emission lines were yielded at the wavelengths of 692, 698, 731, and 745 nm. Under the incident pump power of 50 W and the repetition rate of 4 kHz, the maximum average output powers of 2.4, 2.7, 3.3, and 3.6 W were attained with the pulse durations of 3.4, 3.2, 4.3, and 3.7 ns, respectively, corresponding to the peak powers up to 177, 209, 190, and 245 kW. The results indicate that the Nd:YLF/KGW Raman laser combined with an angle-adjusted BIBO crystal provides a reliable and convenient approach to achieve the selectable multi-wavelength deep-red laser with short pulse duration and high peak power.

High beam quality yellow laser at 588†nm by an intracavity frequency-doubled composite Nd:YVO4 Raman laser.

High beam quality 588 nm radiation was realized based on a frequency-doubled crystalline Raman laser. The bonding crystal of YVO4/Nd:YVO4/YVO4 was used as the laser gain medium, which can accelerate the thermal diffusion. The intracavity Raman conversion and the second harmonic generation were realized by a YVO4 crystal and an LBO crystal, respectively. Under an incident pump power of 49.2 W and a pulse repetition frequency of 50 kHz, the 588 nm power of 2.85 W was obtained with a pulse duration of 3 ns, corresponding to a diode-to-yellow laser conversion efficiency of 5.75% and a slope efficiency of 7.6%. Meanwhile, a single pulse's pulse energy and peak power were 57 µJ and 19 kW, respectively. The severe thermal effects of the self-Raman structure were overcome in the V-shaped cavity, which has excellent mode matching, and combined with the self-cleaning effect of `Raman scattering, the beam quality factor M2 was effectively improved, which was measured optimally to be Mx 2 = 1.207, and My 2 = 1.200, with the incident pump power being 49.2 W.

High-repetition-rate and high-beam-quality all-solid-state nanosecond pulsed deep-red Raman laser.

We report on a high-repetition-rate and high-beam-quality all-solid-state nanosecond pulsed deep-red laser source by intracavity second harmonic generation of the actively Q-switched Nd:YVO4/KGW Raman laser. The polarization of the 1342 nm fundamental laser was aligned with the Ng and Nm axes of KGW crystal for accessing the eye-safe Raman lasers at 1496 and 1526 nm, respectively. With the aid of the elaborately designed V-shaped resonator and the composite Nd:YVO4 crystal, excellent mode matching and good thermal diffusion have been confirmed. Under an optimal pulse repetition frequency of 25 kHz, the average output powers of the Raman lasers at 1496 and 1526 nm were measured to be 3.7 and 4.9 W with the superior beam quality factor of M2 = 1.2, respectively. Subsequently, by incorporating a bismuth borate (BIBO) crystal, the deep-red laser source was able to lase separately two different spectral lines at 748 and 763 nm, yielding the maximum average output powers of 2.5 and 3.2 W with the pulse durations of 15.6 and 11.3 ns, respectively. The resulting beam quality was determined to be near-diffraction-limited with M2 = 1.28.

CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study.

BACKGROUND: Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been described as a biomarker for microglial activation, which were observed increased in a variety of neurological disorders. OBJECTIVE: Our objective was to explore whether genetically determined CSF sTREM2 levels are causally associated with different neurological diseases by conducting a two-sample Mendelian randomization (MR) study. METHODS: Single nucleotide polymorphisms significantly associated with CSF sTREM2 levels were selected as instrumental variables to estimate the causal effects on clinically common neurological diseases, including stroke, Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy and their subtypes. Summary-level statistics of both exposure and outcomes were applied in an MR framework. RESULTS: Genetically predicted per 1 pg/dL increase of CSF sTREM2 levels was associated with higher risk of multiple sclerosis (OR = 1.038, 95%CI = 1.014-1.064, p = 0.002). Null association was found in risk of other included neurological disorders. CONCLUSIONS: These findings provide support for a potential causal relationship between elevated CSF sTREM2 levels and higher risk of multiple sclerosis.

Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.

OBJECTIVE: The immunological features between neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), lacked systemic comparisons. Accordingly, we aimed to investigate immunological differences between NMOSD, MS, and MOGAD. METHODS: Patients with MOGAD, MS, and NMOSD who received immunological tests including cytokine profiles and cytometry analysis of the lymphocyte subgroups were retrospectively reviewed and divided into training and validation sets. Discriminatory models based on immunological data were established to identify optimal classifiers using orthogonal partial least square discriminant analysis (OPLS-DA). Constructed models were tested in another independent cohort. RESULTS: OPLS-DA of the immunological data from 50 patients (26 NMOSD, 14 MS, and 10 MOGAD) demonstrated the discriminatory values of a relatively low level of T-lymphocyte subsets, especially the CD4+ T cells, in MOGAD; a decreased NK cell, eosinophil, and lymphocyte level; an elevated neutrophil-to-lymphocyte ratio in NMOSD; and a declined IFN-γ-producing CD4+ T cells/Th with an increased IL-8 concentration in MS. All the models (NMOSD vs. MS, NMOSD vs. MOGAD, and MS vs. MOGAD) exhibited a significant predictive value and accuracy (>85%). CONCLUSIONS: NMOSD, MS, and MOGAD may be different in pathogenesis, and several immunological biomarkers can serve as potential classifiers clinically.

Anti-N-methyl-D-aspartate receptor encephalitis associated with chronic myelogenous leukemia, causality or coincidence? A case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune paraneoplastic encephalitis, and is primarily associated with ovarian teratomas. Here, we report the first case of a patient diagnosed with chronic myelogenous leukemia (CML) during the recovery phase of anti-NMDAR encephalitis. CASE PRESENTATION: The patient was admitted with fever, headache, and seizures. Brain MRI revealed a cerebrospinal fluid (CSF)-containing arachnoid cyst in the left temporal lobe with no other abnormal signals. EEG showed diffuse background slowing in the delta-theta range. The patient tested positive for anti-NMDAR antibodies in both the serum and CSF. One year after the onset of encephalitis, the patient was referred to the Department of Hematology for extreme leukocytosis. Karyotype analysis showed the presence of Philadelphia chromosome t(9;22)(q34;q11). Quantitative reverse transcriptase PCR analysis further identified BCR/ABL1 fusion transcripts; thus, CML was diagnosed. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-NMDAR encephalitis associated with CML. This report should alert clinicians to consider CML as a malignancy that is possibly associated with limbic encephalitis.

Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system.

In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue homeostasis. Activation of microglia can result in changes in morphology, phagocytosis capacity, and secretion of cytokines. Furthermore, microglial activation also induces changes to cellular energy demand, which is dependent on the metabolism of various metabolic substrates including glucose, fatty acids, and amino acids. Accumulating evidence demonstrates metabolic reprogramming acts as a key driver of microglial immune response. For instance, microglia in pro-inflammatory states preferentially use glycolysis for energy production, whereas, cells in anti-inflammatory states are mainly powered by oxidative phosphorylation and fatty acid oxidation. In this review, we summarize recent findings regarding microglial metabolic pathways under physiological and pathological circumtances. We will then discuss how metabolic reprogramming can orchestrate microglial response to a variety of central nervous system pathologies. Finally, we highlight how manipulating metabolic pathways can reprogram microglia towards beneficial functions, and illustrate the therapeutic potential for inflammation-related neurological diseases.

Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

Intra-cavity diamond Raman laser at 1634 nm.

We demonstrated an eye-safe diamond Raman laser intra-cavity pumped by the 1.3 µm fundamental field for the first time, to the best of our knowledge. The first-Stokes laser at 1634 nm was converted from the 1342 nm fundamental laser, which was produced by an in-band pumped double-end diffusion-bonded a-cut Nd:YVO4 crystal. Under an incident pump power of 21.2 W and an optimal pulse repetition frequency of 25 kHz, the maximum average output power of 2.0 W was obtained with the pulse duration of 5.7 ns and the peak power of 14 kW. The first-Stokes emission was found to be near diffraction limited (M2 ≈ 1.3) and to have a narrow linewidth (∼0.05 nm FWHM; instrument limited).

Nanosecond pulsed deep-red laser source by intracavity frequency-doubled crystalline Raman laser.

We demonstrated a deep-red laser source by intracavity frequency-doubled crystalline Raman laser for the first time, to the best of our knowledge. The actively Q-switched 1314 nm Nd:LiYF4 laser was first converted to the eye-safe Raman laser using a KGd(WO4)2 (KGW) crystal, which was subsequently frequency-doubled in a bismuth borate crystal. Benefiting from the KGW bi-axial properties, the deep-red laser source was able to lase separately at two different spectral lines at 730 and 745 nm. Under an optimal repetition rate of 4 kHz, the maximum average powers of 1.7 and 2.0 W were attained with good beam quality of M2≈1.7. The corresponding pulse durations were determined to be 3.0 and 2.8 ns with the peak powers up to approximately 140 and 180 kW, respectively.