Design, synthesis, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy.

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

Functional reconstruction of the impaired cortex and motor function by hMGEOs transplantation in stroke.

Stroke is the leading cause of death and long-term disability worldwide. But treatments are not available to promote functional recovery, and efficient therapies need to be investigated. Stem cell-based therapies hold great promise as potential technologies to restore function in brain disorders. Loss of GABAergic interneurons after stroke may result in sensorimotor defects. Here, by transplanting human brain organoids resembling the MGE domain (human MGE organoids, hMGEOs) derived from human induced pluripotent stem cells (hiPSCs) into the infarcted cortex of stroke mice, we found that grafted hMGEOs survived well and primarily differentiated into GABAergic interneurons and significantly restored the sensorimotor deficits of stroke mice for a long time. Our study offers the feasibility of stem cell replacement therapeutics strategy for stroke.

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.

Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

Environment-stable sub-100 fs Er: fiber laser with a 3†dB bandwidth of 78†nm.

A robust all polarization-maintaining (PM) passively mode-locked Er-doped fiber laser is demonstrated based on the biased nonlinear amplifier loop mirror (NALM). With a π/2 nonreciprocal free-space phase shifter, stable single pulse mode locking can be obtained at the central wavelength of 1565.7 nm with a 3 dB spectral bandwidth of 24.6 nm in the soliton regime. The repetition rate of the pulse train is 98.13 MHz. The direct output pulse duration is 109 fs, which is nearly transform-limited. After the intracavity dispersion management, the robust self-started mode-locking in the stretched-pulse regime is realized at 1564 nm, and the 3 dB spectral bandwidth reaches up to 78 nm. The repetition rate of the pulse train is 199.6 MHz. In particular, the direct output pulse width is only 77 fs with a low integrated relative intensity noise (RIN) of only 0.0044% (integrated from 1 Hz to 1 MHz). To the best of our knowledge, this is the shortest pulse width directly from the all-PM NALM laser oscillator.

Effects of Drying Methods on the Volatile Compounds of Alliummongolicum Regel.

Allium mongolicum Regel (AMR) is a traditional Mongolian food. Various drying methods play an important role in foodstuff flavor. However, the effect of different drying methods on AMR is limited. In this study, freeze drying (FD), vacuum drying (VD), and hot-air drying (HAD) were applied to dry fresh AMR to a moisture content of 8% (wet basis); headspace gas chromatography mass spectrometry was adopted to identify volatile compounds in AMR; and principal component analysis and fingerprint similarity analysis based on the Euclidean distance was used to distinguish the fresh and three dried treatments. In total, 113 peaks were detected and 102 volatile compounds were identified. Drying causes significant changes to the amounts of volatile compounds in AMR, and the drying method plays a key role in determining which volatile compounds appear. Compared to FD, VD and HAD were more appropriate for drying AMR because the volatile compounds after VD and HAD were closer to those of fresh AMR. These findings can provide a scientific basis to help to preserve future seasonal functional food and aid in Mongolian medicine production.

Total Oxidation of Light Alkane over Phosphate-Modified Pt/CeO2 Catalysts.

Developing efficient catalysts for the total oxidation of light alkane at low temperatures is challenging. In this study, superior catalytic performance in the total oxidation of light alkane was achieved by modulating the acidity and redox property of a Pt/CeO2 catalyst through phosphorus modification. Surface modification with phosphorus resulted in electron withdrawal from Pt, leading to platinum species with high valency and the generation of Brönsted acid sites, leading to increased acidity of the Pt/CeO2 catalyst. Consequently, the ability of the Pt/CeO2 catalyst to activate the C-H bond increased with increasing P content in the catalyst owing to the synergistic effect of Ptδ+-(CeO2-POx)δ- dipolar catalytic sites. In contrast, the redox property of the Pt/CeO2 catalyst weakened at first; subsequently, it was partially restored owing to the recovery of a part of the bare ceria surface with increasing P content. The turnover frequency in propane oxidation over the phosphate-modified Pt/CeO2 catalyst with a P/Ce atomic ratio of 0.06 was 10-fold higher than that over the unmodified Pt/CeO2 catalyst at 220 °C. This comprehensive study not only sheds light on the mechanism underlying the surface modification process but also offers a strategy for realizing higher catalytic activity in the total oxidation of light alkanes.

Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery.

Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.

Generation of pulse-width controllable dissipative solitons and bound solitons by using an all fiber saturable absorber.

A passively mode-locked fiber laser with controllable pulse width is demonstrated by use of an all-fiber saturable absorber based on a hybrid no-core fiber (NCF)-graded index multimode fiber (GIMF) structure incorporated into an Er-doped fiber ring cavity. Such a hybrid NCF-GIMF structure has a tunable intracavity filtering effect. As a result, the mode-locking operation is achieved with controllable pulse width and spectral bandwidth in the normal dispersion regime by only stretching the fiber device. Soliton pulses with the pulse width of 7.7-23 ps are generated, and bound solitons with variable widths are also experimentally demonstrated. The results obtained reveal the versatility and flexibility of the NCF-GIMF structured device in controlling the pulse dynamics for different experimental requirements.

Stretched graded-index multimode optical fiber as a saturable absorber for erbium-doped fiber laser mode locking.

A novel mode-locking method based on the nonlinear multimode interference in the stretched graded-index multimode optical fiber (GIMF) is proposed in this Letter. The simple device geometry, where the light is coupled in and out of the stretched GIMF via single-mode fibers, is demonstrated to exhibit the temporal intensity discrimination required for mode locking. The nonlinear saturable absorber (SA) characteristics of the device are controllable by simply adjusting the strength of the stretching applied. The modulation depth of the device, which consists of ∼23.5 cm GIMF, is tuned from 10.37% to 22.27%. Such a simple SA enables the wavelength-switchable mode-locking operation in a ring Er-doped fiber laser, and ultrafast pulses with a pulse width of 506 fs at 1572.5 nm and 416 fs at 1591.4 nm were generated. The versatility and simplicity of the SA device, together with the possibility of scaling the pulse energy, make it highly attractive in ultrafast photonics.

The telomerase inhibitor AZT enhances differentiation and prevents overgrowth of human pluripotent stem cell-derived neural progenitors.

Human pluripotent stem cell (hPSC)-based cell-replacement therapy has emerged as a promising approach for addressing numerous neurological diseases. However, hPSC transplantation has the potential to cause human cell overgrowth and cancer, which represents a major obstacle to implementing hPSC-based therapies. Inhibition of the overgrowth of transplanted cells could help reduce the risk for hPSC transplantation-induced tumorigenesis. In this study, we report that the telomerase inhibitor azidothymidine (3'-azido-3'-deoxythymidine; AZT) enhances the differentiation of cortical neurons and significantly suppresses the proliferation of hPSC-derived cortical progenitors. Using human embryonic stem cells and induced pluripotent stem cells in culture, we found that AZT effectively reduces the number of dividing progenitors without inducing cell death. Furthermore, AZT promoted differentiation of cortical progenitors and maturation of cortical neurons. Of note, AZT-pretreated, hPSC-derived neural progenitors exhibited decreased proliferation and increased differentiation into cortical neurons when transplanted into the mouse brain. In summary, our findings indicate that AZT prevents the overgrowth of hPSC-derived neural precursors and enhances the differentiation of cortical neurons in both cell cultures and hPSC-transplanted mouse brain. We propose that our work could inform clinical applications of hPSC-based cell therapy.

Saturable absorber based on a single mode fiber - graded index fiber - single mode fiber structure with inner micro-cavity.

An Er-doped mode-locked fiber laser with a saturable absorber based on single mode - graded index multimode - single mode fiber (SMF-GIMF-SMF) with inner micro-cavity is demonstrated. The modulation depth of the saturable absorber was measured to be 1.9% when the SMF-GIMF-SMF structure is bent to a certain state. Such a simple saturable absorber enables the mode-locking operation in a ring Er-doped fiber laser and ultrafast pulses with pulse energy of 0.026 nJ and pulse width of 528 fs at the fundamental repetition rate of 14.34 MHz can be generated. In addition, the harmonic mode-locking operation can also be achieved.

Enhanced derivation of human pluripotent stem cell-derived cortical glutamatergic neurons by a small molecule.

Human pluripotent stem cells (hPSCs) play important role in studying the function of human glutamatergic neurons and related disease pathogenesis. However, the current hPSC-derived cortical system produced a significant number of inhibitory GABAergic neurons that reduced the purity of excitatory neurons. In this study, we established a robust hPSC-derived cortical neurogenesis system by applying the SHH inhibitor cyclopamine. Cyclopamine specified the dorsal cortical fate in a dose-dependent manner and enhanced the generation of cortical glutamatergic neurons, expressing PAX6, TBR1, TBR2, CTIP2, SATB2, and vesicular glutamate transporters (vGLUT). In contrast, the ventral patterning was inhibited and the GABAergic neurons were significantly reduced to 12% with the treatment of cyclopamine. In addition, we applied our current method to generate trisomy 21 iPSC-derived glutamatergic neurons that showed a robust reduction of vesicular glutamate transporters in the glutamatergic neurons with trisomy 21, revealing the developmental deficits in cortical glutamatergic neurons. Our method enriched the generation of cortical glutamatergic neurons which may facilitate the study of human neurological diseases and cell therapy.

Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells.

BACKGROUND: Basal forebrain cholinergic neurons (BFCNs) play critical roles in learning, memory and cognition. Dysfunction or degeneration of BFCNs may connect to neuropathology, such as Alzheimer's disease, Down's syndrome and dementia. Generation of functional BFCNs may contribute to the studies of cell-based therapy and pathogenesis that is related to learning and memory deficits. NEW METHOD: Here we describe a detail method for robust generation of BFCNs from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). In this method, BFCN progenitors are patterned from hESC or hiPSC-derived primitive neuroepithelial cells, with the treatment of sonic hedgehog (SHH) or combination with its agonist Purmorphamine, and by co-culturing with human astrocytes. RESULTS: At day 20, ∼90% hPSC-derived progenitors expressed NKX2.1, which is a transcriptional marker for MGE. Moreover, around 40% of NKX2.1+ cells co-expressed OLIG2 and ∼15% of NKX2.1+ cells co-expressed ISLET1, which are ventral markers. At day 35, ∼40% neurons robustly express ChAT, most of which are co-labeled with NKX2.1, ISLET1 and FOXG1, indicating the basal forebrain-like identity. At day 45, these neurons express mature neuronal markers MAP2, Synapsin, and VAChT. COMPARISON WITH EXISTING METHOD(S): In this method, undefined conditions including genetic modification or cell-sorting are avoided. As a choice, feeder free conditions are used to avoid ingredients of animal origin. Moreover, Purmorphamine can be substituted for SHH to induce ventral progenitors effectively and economically. CONCLUSION: We provide an efficient method to generate BFCNs from multiple hPSC lines, which offers the potential application for disease modeling and pharmacological studies.

Efficient generation of region-specific forebrain neurons from human pluripotent stem cells under highly defined condition.

Human pluripotent stem cells (hPSCs) have potential to differentiate to unlimited number of neural cells, which provide powerful tools for neural regeneration. To date, most reported protocols were established with an animal feeder system. However, cells derived on this system are inappropriate for the translation to clinical applications because of the introduction of xenogenetic factors. In this study, we provided an optimized paradigm to generate region-specific forebrain neurons from hPSCs under a defined system. We assessed five conditions and found that a vitronectin-coated substrate was the most efficient method to differentiate hPSCs to neurons and astrocytes. More importantly, by applying different doses of purmorphamine, a small-molecule agonist of sonic hedgehog signaling, hPSCs were differentiated to different region-specific forebrain neuron subtypes, including glutamatergic neurons, striatal medium spiny neurons, and GABA interneurons. Our study offers a highly defined system without exogenetic factors to produce human neurons and astrocytes for translational medical studies, including cell therapy and stem cell-based drug discovery.

Intensity evaluation using a femtosecond pulse laser for absolute distance measurement.

In this paper, we propose a method of intensity evaluation based on different pulse models using a femtosecond pulse laser, which enables long-range absolute distance measurement with nanometer precision and large non-ambiguity range. The pulse cross-correlation is analyzed based on different pulse models, including Gaussian, Sech(2), and Lorenz. The DC intensity and the amplitude of the cross-correlation patterns are also demonstrated theoretically. In the experiments, we develop a new combined system and perform the distance measurements on an underground granite rail system. The DC intensity and amplitude of the interference fringes are measured and show a good agreement with the theory, and the distance to be determined can be up to 25 m using intensity evaluation, within 64 nm deviation compared with a He-Ne incremental interferometer, and corresponds to a relative precision of 2.7×10(-9).

Absolute distance measurement by intensity detection using a mode-locked femtosecond pulse laser.

We propose an interferometric method that enables to measure a distance by the intensity measurement using the scanning of the interferometer reference arm and the recording of the interference fringes including the brightest fringe. With the consideration of the dispersion and absorption of the pulse laser in a dispersive and absorptive medium, we investigate the cross-correlation function between two femtosecond laser pulses in the time domain. We also introduce the measurement principle. We study the relationship between the position of the brightest fringe and the distance measured, which can contribute to the distance measurement. In the experiments, we measure distances using the method of the intensity detection while the reference arm of Michelson interferometer is scanned and the fringes including the brightest fringe is recorded. Firstly we measure a distance in a range of 10 µm. The experimental results show that the maximum deviation is 45 nm with the method of light intensity detection. Secondly, an interference system using three Michelson interferometers is developed, which combines the methods of light intensity detection and time-of-flight. This system can extend the non-ambiguity range of the method of light intensity detection. We can determine a distance uniquely with a larger non-ambiguity range. It is shown that this method and system can realize absolute distance measurement, and the measurement range is a few micrometers in the vicinity of Nl(pp), where N is an integer, and lpp is the pulse-to-pulse length.

High-finesse cavity external optical feedback DFB laser with hertz relative linewidth.

We report hertz level relative linewidth distributed feedback diode lasers with external optical feedback from a high finesse F-P cavity, and demonstrate the efficient phase noise suppression and laser linewidth reduction of the optical feedback technique. The laser phase noise is dramatically suppressed throughout the measurement frequency range. Especially at the Fourier frequency of 17 kHz, approximately the linewidth of the F-P reference cavity, the laser phase noise is significantly suppressed by more than 92 dB. Above this Fourier frequency, the noise maintains a white phase noise plateau as low as -124.4 dBc/Hz. The laser's FWHM linewidth is reduced from 7 MHz to 4.4 Hz, and its instantaneous linewidth is 220 mHz in the Lorentzian fitting.

Characterization of the carrier envelope offset frequency from a 490 MHz Yb-fiber-ring laser.

We present the characterization of the carrier envelope offset frequency of 490 MHz femtosecond Yb-fiber ring laser. After amplification and compression, 1.7 W 90 fs pulses were produced for octave-span-spectrum generation from 600 nm to 1300 nm. More than 30 dB S/N ratio carrier envelope offset frequency signal was measured through a quasi-common-path interferometer.

[Joint time-frequency analysis for removing the spectral interference of terahertz].

Conventional Fourier-transform mixes the frequency components of the entire temporal terahertz waveform in one frequency domain; therefore, it cannot distinguish the terahertz frequency in the main pulse from the noise frequency in the pulse tail. Thus traditional Fourier-transform produces inconsistent spectra from different scanning lengths of terahertz pulse. And the interference spectrum appears when the THz echo pulse is recorded. The authors applied wavelet-transform and removed the inconsistent spectra and the interference spectra. Wavelet-transform technique exhibited the local frequency of THz in different time locations. This technique would find applications in THz time-resolved spectroscopy.

Emission spectrum broadening of Nd:YVO(4) with femtosecond laser pulse processing.

The observation of emission spectrum broadening of Nd:YVO(4) by femtosecond laser pulse processing is reported. This result opens the possible way of sub-ps pulse generation from Nd ion doped crystals with better physical qualities than that of glass based laser gain materials.