Chemical synthesis and functional evaluation of glycopeptides and glycoproteins containing rare glycosyl amino acid linkages.

Covering: 1987 to 2023Naturally existing glycoproteins through post-translational protein glycosylation are highly heterogeneous, which not only impedes the structure-function studies, but also hinders the development of their potential medical usage. Chemical synthesis represents one of the most powerful tools to provide the structurally well-defined glycoforms. Being the key step of glycoprotein synthesis, glycosylation usually takes place at serine, threonine, and asparagine residues, leading to the predominant formation of the O- and N-glycans, respectively. However, other amino acid residues containing oxygen, nitrogen, sulfur, and nucleophilic carbon atoms have also been found to be glycosylated. These diverse glycoprotein linkages, occurring from microorganisms to plants and animals, play also pivotal biological roles, such as in cell-cell recognition and communication. The availability of these homogenous rare glycopeptides and glycoproteins can help decipher the glyco-code for developing therapeutic agents. This review highlights the chemical approaches for assembly of the functional glycopeptides and glycoproteins bearing these "rare" carbohydrate-amino acid linkages between saccharide and canonical amino acid residues and their derivatives.

Photothermal Responsive Digital Polymerase Chain Reaction Resolving Exosomal microRNAs Expression in Liver Cancer.

Exosomal microRNAs have been studied as a good source of noninvasive biomarkers due to their functions in genetic exchange between cells and have been already well documented in many biological activities; however, inaccuracy remains a key challenge for liver cancer surveillance. Herein, a versatile duplex photothermal digital polymerase chain reaction (PCR) strategy combined with a lipid nanoparticle-based exosome capture approach is proposed to profile microRNAs expression through a 3-h easy-to-operate process. The microfluidically-generated molybdenum disulfide-nanocomposite-doped gelatin microcarriers display attractive properties as a 2-4 °C s-1 ramping-up rate triggered by near-infrared and reversible sol-gel transforming in step with PCR activation. To achieve PCR thermocycling, the corresponding irradiation coordinating with fan cooling are automatically performed via a homemade control module with programs. Thus, taking the multiplexing capability of dual-color labeling, 19-31 folds higher in exosomal microRNA-200b-3p and microRNA-21-5p, and tenfold lower in microRNA-22-3p expressions relative to the control microRNA-26a-5p are quantified in two liver cancer cells (Huh7 and HepG2) than in those from the healthy cells. It is believed that this exosomal microRNA genotyping method would be highly applicable for liver cancer diagnostics.

Aligned electrospun fiber film loaded with multi-enzyme mimetic iridium nanozymes for wound healing.

A film with elaborate microstructures that offers biomimetic properties and multi functionalities is highly desired in wound healing. Here, we develop an aligned hydrogel fiber film integrated with multi-active constituents to promote wound healing. Such fiber films are designed and constructed by photo-crosslinking the methacrylate gelatin (GelMA) doped with silver nanoparticles (Ag NPs) and iridium nanoparticles coated with polyvinylpyrrolidone (PVP-Ir NPs) in the precursor solution using electrospinning. The nature of GelMA hydrogel and the aligned arrangement of nanofibers endow the film with high-water content, self-degradability, improved bionic characteristics, oriented cell growth, and improved cell proliferation and migration. Moreover, the encapsulated nanozymes and Ag NPs offer the fiber film with superior reactive oxygen species (ROS) scavenging and antibacterial capability. The infected wound model shows that the multi-active hydrogel fiber film can reduce inflammation by killing bacteria and decomposing ROS, which accelerates the growth of new blood vessels and granulation tissue. Benefitting from these features, the versatile aligned GelMA fiber film demonstrates the clinically translational potential for wound healing.

PGC-1α activates SIRT3 to modulate cell proliferation and glycolytic metabolism in breast cancer.

Breast cancer is the leading cause of death among women. PGC-1α plays an important role in the regulation of metabolic reprogramming in cancer cells. SIRT3 has significant implications for tumor growth. In this study, we explored the roles of PGC-1α and SIRT3 in cell proliferation and mitochondrial energy metabolism alterations in breast cancer cells. The expression patterns of PGC-1α and SIRT3 were examined using qRT-PCR and western blotting analysis. MCF-7 and MDA-MB-231 cells were infected with adenovirus to overexpress or knock down the expression of PGC-1α and SIRT3. Cell viability and apoptosis were analyzed by CCK-8 and flow cytometry, respectively. Hexokinase 2, pyruvate kinase activities, as well as NAD+/NADH ratio and ATP concentration, were assessed by commercial kits. Glucose consumption was measured using the glucose oxidase method and lactic acid concentration was detected by lactate dehydrogenase kit. Expression levels of PGC-1 and SIRT3 were much lower in breast cancer patients, compared with the normal controls. Overexpression of PGC-1α or SIRT3 both significantly promoted the apoptosis and inhibited the proliferation in MCF-7 and MDA-MB-231 cells. Additionally, PGC-1α or SIRT3 also induced the inhibition of glycolysis metabolism. Moreover, the expression of SIRT3 was positively regulated by PGC-1α. Silencing SIRT3 partly reversed the negative effects of PGC-1α on glycolytic metabolism. These findings demonstrated that PGC-1α/SIRT3 regulated cell proliferation and apoptosis of breast cancer through altering glycolysis, which may provide novel therapeutic strategies for breast cancer.

CYT387, a Novel JAK2 Inhibitor, Suppresses IL-13-Induced Epidermal Barrier Dysfunction Via miR-143 Targeting IL-13Rα1 and STAT3.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influencing not only children but also adults. It is well-known that AD has a complex pathogenesis without effective therapy. Herein, we explored the function and mechanism of CYT387, a novel JAK2 inhibitor, on epidermal barrier damage. HaCaT cells exposed with high-concentration Ca2+ (1.8 mM) for 14 days were recruited for the model of keratinocytes (KC). The cell model of skin barrier damage was induced by IL-13, and KC markers such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL) were detected to judge the success of the model. In this study, we found that miR-143 was lowly expressed whereas IL-13Rα1 was highly expressed in blood cells of patients with AD, indicating their negative correlation. Moreover, IL-13 treatment down-regulated miR-143 and up-regulated activated JAK2 and STAT3 phosphorylation, which was reversed by CYT387 administration. The dual-luciferase reporter assay verified that miR-143 could directly bind to 3'-UTR of IL-13Rα1, as well as STAT3. Furthermore, the function of CYT387 in the skin barrier damage induced by IL-13 was abolished by miR-143 inhibitor. Thus, CYT387 might alleviate IL-13-induced epidermal barrier damage via targeting IL-13Rα1 and STAT3 by miR-143 to repress inflammation. These findings revealed that the protective effects and the underlying mechanisms of CYT387 in AD, which provided evidence that miR-143 may be a novel therapeutic target for AD.

High-power repetition rate- and pulse width-tunable 589†nm versatile laser for adaptive optical systems.

Compact high-power yellow laser is a critical part for sodium beacon adaptive optical systems. A narrow-linewidth quasi-continuous-wave (QCW) solid-state 589 nm laser with high-power and high beam quality simultaneously is investigated here, operating in hundreds-microsecond pulse duration with a tunable repetition rate of 400 to 1 kHz, which is flexible to allow the telescope to move in observing direction. The laser source is based on employing sum-frequency generation between 1319 and 1064 nm QCW Nd:YAG amplifiers. For a 100 µs pulse duration and 400 Hz repetition rate, the yellow laser provides a highest output power of 86.1 W with beam quality M2 = 1.37. The central wavelength can be precisely tuned to sodium-D2a line at 589.159 nm with a ∼440 MHz linewidth. This is the maximum power-reported for all-solid-state sodium guide star laser demonstrated to date. The result represents a key step toward solving the requirement of multi-conjugate adaptive optics for large adaptive optical telescopes.

High-repetition-rate 100 W level sodium beacon laser for a multi-conjugate adaptive optics system.

A 100 W level kilohertz repetition-rate microsecond (µs)-pulse all-solid-state sodium beacon laser at 589 nm is demonstrated for the first time, to the best of our knowledge, via combining two independent µs-pulsed lasers. Each beamlet is generated by the sum-frequency mixing of pulsed 1064 and 1319 nm lasers in a lithium triborate (LBO) crystal, which operate at 500 Hz pulse repetition frequency with 61 W $p$p-polarized and 53 W $s$s-polarized output, respectively. An incoherent sequence combining technology of polarized laser beams is employed to add the two beamlets. The average power of the combined beam is up to 107.5 W with a combining efficiency of 94.3%. The combined beam has a 1 kHz repetition rate with ${\sim}{120}\;\unicode{x00B5} {\rm s}$∼120µs pulse duration and beam quality ${M^2} = {1.41}$M2=1.41. The central wavelength with a linewidth of ${\sim}{0.3}\;{\rm GHz}$∼0.3GHz is locked to a sodium ${{\rm D}_{2a}}$D2a absorption line. To the best of our knowledge, this is a record-high power operating at kilohertz for µs-pulsed solid-state sodium beacon lasers.

30 W single-frequency continuous-wave master oscillator power amplifier laser at 1342 nm.

We present a power-scalable high-power single-frequency continuous-wave 1342 nm master oscillator power amplifier (MOPA) system that consists of a polarized single-frequency 1342 nm LD seed laser, a Raman fiber preamplifier, and a three-stage ${\rm Nd}:{{\rm YVO}_4}$Nd:YVO4 power amplifier. The single-frequency output power of 30 W at 1342 nm is achieved with the beam quality factors ${{\rm M}^{2\:}} = {1}.{26}$M2=1.26, and the power stability for 1 h is better than ${\pm }\;{0}.{5}\% $±0.5%.

Void-free bonding for a large slab laser crystal.

A void-free bonding technique was demonstrated for a large slab Nd: YAG crystal with a bonding surface dimension of ∼160mm×70mm. By using the novel fluxless oxide layer removal technology, the indium-oxide barrier problem was resolved. With the help of electrochemical-polished indium solder and a plasma-cleaned heat sink, the solderability of the indium was enhanced; in particular, the contact angle of the solder was improved from 51° to 31°. With the largest-bonding-size slab, a single-slab laser created a maximum output power of 7.3 kW under an absorbed pump power of 12.8 kW, corresponding to an optical to optical efficiency of 57% and a slope conversion of 67.8%. By detecting the wavefront of the interferometer before and after bonding, the RMS of wavefront was 0.192λ and 0.434λ (λ=633nm), respectively. To the best of our knowledge, this is the largest void-free bonding size for a laser slab and the highest output power achieved from a single-slab crystal laser oscillator.

Watt level laser source for a polychromatic laser guide stars: double resonant fluorescence from 3S1/2-3P3/2-3D5/2 transition of sodium atoms.

The polychromatic laser guide star (PLGS) is one of the solutions proposed to measure the differential atmospheric tip-tilt. A watts-level microsecond pulse all solid state laser source with two wavelengths at 589 and 819.7 nm are developed to perform a proof-of-concept on-sky test for what is believed to be the first time. By sum-frequency of 1319 and 1064 nm, a 44 W maximum average output power at 589.159 nm is generated with the pulse width of ~90 µs at 500 Hz, the linewidth of 0.46 pm, and the beam quality of M2 = 1.50. Meanwhile, a 2.4 W average output power is achieved operating at 819.710 nm with the pulse width of ~25 µs at 500 Hz, the linewidth of 0.8 pm, and beam quality factor of M2 = 1.20, which is end-pumped by a frequency-doubled 1064 nm Nd:YAG laser. Moreover, double resonant fluorescence in sodium cell with two step excitation of sodium atom from 3S1/2 to 3D5/2 via 3P3/2 level is observed clearly by tuning the wavelength of 589 and 819.7 nm beams. In the proof-of-principle experiment, it is preliminarily verified that this laser system is expected to be applied to the sky experiment.

Pulse duration adjusted by changing the cavity length with a multi-pass cavity in a Q-switched Nd:YAG laser.

We report a compact, long nanosecond (ns) pulse duration stretched laser source by a multi-pass cavity (MPC). Based on the combination of the MPC and pump power, a high-power high beam quality 1064 nm Q-switched Nd:YAG laser with a pulse duration adjustable over the range of 160-1000 ns was obtained at a pulse repetition frequency of 10 kHz for the first time, to the best of our knowledge. At a typical pulse width of 560 ns, an average output power of 10.6 W was successfully achieved. The beam quality factor M2 was measured to be 1.45 with a good Gaussian mode.

Picosecond slab regenerative amplifier using a large fundamental mode stable-unstable hybrid cavity.

Slab gain media with large aspect ratios were difficult to be adopted in ultrafast regenerative amplifiers (RAs) due to the obstacle of mode matching with the seed beam. We proposed that an unstable cavity could be employed to solve this difficulty by taking the advantage of its large fundamental mode volume. In this way, an Nd:YVO4 slab-based picosecond RA has been successfully demonstrated using a stable-unstable hybrid cavity. The maximum average output power of 10.5 W was achieved at the repetition rate of 10 kHz. The beam quality factor M2 was measured to be 1.54 in the stable direction and 2.26 in the unstable direction.

Incidence and types of HIV-1 drug resistance mutation among patients failing first-line antiretroviral therapy.

OBJECTIVE: This study aims to investigate the prevalence and types of drug resistance mutations among patients failing first-line antiretroviral therapy (ART). METHODS: Plasma samples from 112 patients with human immunodeficiency virus-1 (HIV-1) were collected for virus RNA extract and gene amplification. The mutations related to drug resistance were detected and the incidence was statistically analyzed, and the drug resistance rate against common drugs was also evaluated. RESULTS: 103 cases were successfully amplified, and the main drug resistance mutations in the reverse transcriptase (RT) region were M184V (50.49%), K103N (28.16%), Y181C (25.24%), and K65R (27.18%), while no drug main resistance mutation was found in the protease (PR) region. The incidence of drug resistance mutations was significantly different among patients with different ages, routes of infection, duration of treatment, initial ART regimens and viral load. The drug resistance rate to the common drugs was assessed, including Efavirenz (EFV, 71.84%), Nevirapine (NVP, 74.76%), Lamivudine (3TC, 66.02%), Zidovudine (AZT, 4.85%), Stavudine (D4T, 16.51%), and Tenofovir (TDF, 21.36%). CONCLUSION: The drug resistance mutations to NRTIs and NNRTIs are complex and highly prevalent, which was the leading cause of first-line ART failure. This study provides significant theoretical support for developing the second-line and third-line therapeutic schemes.

Effect of root exudates of intercropping Vicia faba and Arabis alpina on accumulation and sub-cellular distribution of lead and cadmium.

A field experiment in which a hyperaccumulator (Arabis alpina) was intercropped with winter crop (Vicia faba), was conducted to understand effect of the root exudates on the content and accumulated amounts, sub-cellular distribution of Cd and Pb of the intercropped plants during the ripening period of V. faba (120 d after sowing). The results showed that contents of soluble sugars exuded from the roots of intercropped A. alpina were 67.6% less than that of the monocropped plant, whereas contents of free amino acids was 57.9% greater. The total contents of organic acids exuded from roots of intercropped A. alpina and V. faba were 578.8% and 37.8% greater than that of monocropped plants, respectively. The contents of tartaric acid and malic acid exuded by roots of intercropped A. alpina were greater 31.9 times and 15.9 times than those of monocropped A. alpina, respectively. The contents and accumulated amounts of Cd and Pb in intercropped A. alpina were greater than those of monocropped A. alpina. The contents of Pb bound to organic matter in cell walls, cytoplasm and organelles of intercropped plants were greater than those of monocropped plants. These results demonstrate that increases in accumulated amounts of Pb and Cd caused by intercropping were closely related to migration of Cd and Pb in plants mediated by the composition and content of the root exudates.

30.5-µJ, 10-kHz, picosecond optical parametric oscillator pumped synchronously and intracavity by a regenerative amplifier.

We have proposed a novel approach to realize a high-energy ultrafast optical parametric oscillator (OPO) by intracavity pumping in a regenerative amplifier. In this way, we have experimentally demonstrated an unprecedented pulse energy of 30.5 µJ from a 1.5-µm singly resonant synchronously pumped OPO at a pulse repetition rate of 10 kHz with a pulse width of 7.0 ps. To the best of our knowledge, this is the highest pulse energy from an ultrafast laser OPO.

High-energy single-frequency 167 nm deep-ultraviolet laser.

We report a high-energy single-frequency deep-ultraviolet (DUV) solid-state laser at 167.079 nm by the eighth-harmonic generation of a diode-pumped Nd:LGGG laser. A maximum DUV laser output energy of 1.5 µJ at a 5 Hz repetition rate with a 200 µs pulse duration is achieved. The central wavelength of the DUV laser is located at 167.079 nm and can be finely tuned from 167.075 to 167.083 nm. The linewidth is estimated to be 0.025 pm. To the best of our knowledge, this is the first Letter reporting a high-energy single-frequency solid-state DUV laser below 170 nm. The successful demonstration of the high-energy single-frequency DUV laser source with the unique wavelength is useful for direct detection of a Al+27 ion via resonance fluorescence in a multi-ion optical clock.

Synthesis of Surface-Modification-Oriented Nanosized Molybdenum Disulfide with High Peroxidase-Like Catalytic Activity for H2 O2 and Cholesterol Detection.

Abnormal H2 O2 and cholesterol levels are closely related to many diseases. This work reports a facile process for the synthesis of oxidized glutathione (GSSG)-modified MoS2 nanosheets (MoS2 -GSSG NSs). The biocompatible MoS2 -GSSG NSs have good dispersibility and high affinity to the substrate 3,3',5,5'-tetramethylbenzidine (TMB), which is beneficial for improving peroxidase-like catalytic activity of MoS2 . The high peroxidase-like activity of MoS2 -GSSG NSs was applied as a robust nanoplatform for low-cost, rapid, and highly effective colorimetric detection of H2 O2 and total/free cholesterol. Moreover, the peroxidase-like catalytic mechanism was studied by the steady-state kinetics method. The catalytic activity was remarkably high at a wide range of pH (2.4-7.0) and temperature values (25-70 °C). The cholesterol was catalyzed by cholesterol oxidase (ChOx) in the presence of O2 to generate H2 O2 , which oxidized TMB to generate a blue-colored product (oxTMB) under the catalysis of MoS2 -GSSG NSs. The detection limit (DL) of total cholesterol and H2 O2 was as low as 5.36 and 0.51 µm, respectively. The linear ranges for detecting cholesterol and H2 O2 were from 5.36 to 800 µm and from 0.51 to 50 µm, respectively. This method was also successfully applied to the detection of cholesterol in serum. The detection concentration of total cholesterol was consistent with that of the value detected by the blood biochemical method used in the clinic.

High-efficiency UV generation at 266 nm in a new nonlinear optical crystal NaSr3Be3B3O9F4.

266 nm laser output in NaSr3Be3B3O9F4 crystal by the fourth harmonic generation process with a picosecond mode-locked Nd-based YAG laser has been done for the first time. When the input pumping energy was 870 µJ at 532 nm, a 280 µJ 266 nm UV laser was obtained and the corresponding conversion efficiency was 35.9%. Further investigations identified that NaSr3Be3B3O9F4 has a large acceptance angle width of 0.47 (mrad • cm), a small walk-off angle of 35.43 mrad and a large deff as 0.62 pm/V for the fourth harmonic generation. These results indicate that NSBBF is applicable for high-power 266 nm laser generation.

Picosecond mid-infrared optical parametric amplifier based on LiInSe2 with tenability extending from 3.6 to 4.8 µm.

A picosecond (ps) mid-infrared (MIR) optical parametric amplifier (OPA) with LiInSe2 crystal was demonstrated for the first time. The MIR OPA was pumped by a 30 ps 1064 nm Nd:YAG laser and injected by a barium boron oxide (BBO)-based widely tunable near-infrared seed. A maximum idler pulse energy of 433 µJ at 4 µm has been obtained under a pump energy of 17 mJ, and the corresponding pulse duration was estimated to be ~13 ps. To our knowledge, this is the highest single pulse energy generated by LiInSe2 crystal. Furthermore, an idler spectrum tuning from 3.6 to 4.8 µm was investigated at fixed pump energy of 15 mJ.