Circulating Tumor Cell Phenotype Detection and Epithelial-Mesenchymal Transition Tracking Based on Dual Biomarker Co-Recognition in an Integrated PDMS Chip.

Circulating tumor cells (CTCs) are widely considered as a reliable and promising class of markers in the field of liquid biopsy. As CTCs undergo epithelial-mesenchymal transition (EMT), phenotype detection of heterogeneous CTCs based on EMT markers is of great significance. In this report, an integrated analytical strategy that can simultaneously capture and differentially detect epithelial- and mesenchymal-expressed CTCs in bloods of non-small cell lung cancer (NSCLS) patients is proposed. First, a commercial biomimetic polycarbonate (PCTE) microfiltration membrane is employed as the capture interface for heterogenous CTCs. Meanwhile, differential detection of the captured CTCs is realized by preparing two distinct CdTe quantum dots (QDs) with red and green emissions, attached with EpCAM and Vimentin aptamers, respectively. For combined analysis, a polydimethylsiloxane (PDMS) chip with simple structure is designed, which integrates the membrane capture and QDs-based phenotype detection of CTCs. This chip not only implements the analysis of the number of CTCs down to 2 cells mL-1, but enables EMT process tracking according to the specific signals of the two QDs. Finally, this method is successfully applied to inspect the correlations of numbers or proportions of heterogenous CTCs in 94 NSCLS patients with disease stage and whether there is distant metastasis.

Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity.

Autophagy is a degradational pathway with pivotal roles in cellular homeostasis and survival, including protection of neurons in the central nervous system (CNS). The significance of autophagy as antiviral defense mechanism is recognized and some viruses hijack and modulate this process to their advantage in certain cell types. Here, we present data demonstrating that the human neurotropic herpesvirus varicella zoster virus (VZV) induces autophagy in human SH-SY5Y neuronal cells, in which the pathway exerts antiviral activity. Productively VZV-infected SH-SY5Y cells showed increased LC3-I-LC3-II conversion as well as co-localization of the viral glycoprotein E and the autophagy receptor p62. The activation of autophagy was dependent on a functional viral genome. Interestingly, inducers of autophagy reduced viral transcription, whereas inhibition of autophagy increased viral transcript expression. Finally, the genotype of patients with severe ocular and brain VZV infection were analyzed to identify potential autophagy-associated inborn errors of immunity. Two patients expressing genetic variants in the autophagy genes ULK1 and MAP1LC3B2, respectively, were identified. Notably, cells of both patients showed reduced autophagy, alongside enhanced viral replication and death of VZV-infected cells. In conclusion, these results demonstrate a neuro-protective role for autophagy in the context of VZV infection and suggest that failure to mount an autophagy response is a potential predisposing factor for development of severe VZV disease.

Single-frequency DBR lasing by integrating FBGs into germanium-free photosensitive highly Yb3+-doped silica fibers.

Monolithic distributed Bragg reflector (DBR) cavity which directly integrates fiber Bragg gratings (FBGs) into the photosensitive RE-doped fibers is a promising configuration in constructing compact and efficient single frequency fiber lasers (SFFLs). Yet, the doping level of rare-earth (RE) ions has generally to be sacrificed in the classical Ge-photosensitized RE-doped silica fibers because of the dramatic refractive index increase caused by the introduction of Ge. Here, we demonstrate an approach to realize the trade-off between photosensitivity and RE doping concentration. We validate that the addition of a small amount of cerium (0.37wt.%) instead of Ge could photosensitize Yb3+-doped silica fiber (YDF), while maintaining fiber numerical aperture (NA) at 0.12 under a high 2.5-wt.% Yb doping level. Based on the short monolithic DBR cavity constructed by this germanium-free photosensitive highly YDF, a 1064 nm fiber laser with a 48.6% slope efficiency and an over 200 mW power on two orthogonally polarized modes could be realized. Further stable and linear-polarized 1064 nm SFFL is also demonstrated in a designed monolithic polarization maintaining cavity with an output power of 119 mW and an efficiency of 26.4%. Our results provide an alternative way to develop photosensitive highly RE-doped fibers towards monolithic laser cavity application.

Er-doped silicate fiber amplifiers in the L-band with flat gain.

We demonstrated an efficient way to enhance and flatten the emission cross sections of Er3+ ions at the L-band in the silicate fiber amplifier by increasing Mg2+ (up to 22.5 mol%) with high field strength. High values of Er3+ concentration, lifetime, and L-band emission cross section were achieved in our silicate fibers. Particularly, the flatness at the L-band was achieved to be 0.8 dB, and a high gain coefficient at 1625 nm (4.7 dB/m) was demonstrated by pumping meter-scale Er-silicate fibers. The as-prepared Er-silicate fibers are attractive for the L-band fiber amplifier.

Transcriptome-wide high-throughput m6 A sequencing of differential m6 A methylation patterns in the decidual tissues from RSA patients.

Recurrent spontaneous abortion (RSA) is characterized by two or more consecutive pregnancy losses in the first trimester of pregnancy, experienced by 5% of women during their reproductive age. As a complex pathological process, the etiology of RSA remains poorly understood. Recent studies have established that gene expression changes dramatically in human endometrial stromal cells (ESCs) during decidualization. N6-methyladenosine (m6 A) modification is the most prevalent epigenetic modification of mRNA in eukaryotic cells and it is closely related to the occurrence and development of many pathophysiological phenomena. In this study, we first confirmed that high levels of m6 A mRNA methylation in decidual tissues are associated with RSA. Then, we used m6 A-modified RNA immunoprecipitation sequence (m6 A-seq) and RNA sequence (RNA-seq) to identify the differentially expressed m6 A methylation in decidual tissues from RSA patients and identified the key genes involved in abnormal decidualization by bioinformatics analysis. Using m6 A-seq, we identified a total of 2169 genes with differentially expressed m6 A methylation, of which 735 m6 A hypermethylated genes and 1434 m6 A hypomethylated genes were identified. Further joint analysis of m6 A-seq and RNA-seq revealed that 133 genes were m6 A modified with mRNA expression. GO and KEGG analyses indicated that these unique genes were mainly enriched in environmental information processing pathways, including the cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway. In summary, this study uncovered the transcriptome-wide m6 A modification pattern in decidual tissue of RSA, which provides a theoretical basis for further research into m6 A modification and new therapeutic strategies for RSA.

Theoretical and experimental investigation of Al3+ ion-suppressed phase-separation structures in rare-earth-doped high-phosphorus silica glasses.

Rare-earth-doped silica-based composite glasses (Re-SCGs) are widely used as high-quality laser gain media in defense, aerospace, energy, power, and medical applications. The variable regional chemical environments of Re-SCGs can induce new photoluminescence properties of rare-earth ions but can cause the selective aggregation of rare-earth ions, limiting the application of Re-SCGs in the field of high-power lasers. Here, topological engineering is proposed to adjust the degree of cross-linking of phase-separation network chains in Re-SCGs. A combination of experimental and theoretical characterization techniques suggested that the selective aggregation of rare-earth ions originates from the formation of phase-separated structures in glasses. The decomposition of nanoscale phase separation structures to the sub-nanometer scale, enabled by incorporating Al3+ ions, not only maintains the high luminescence efficiency of rare earth ions but also increases light transmittance and reduces light scattering. Furthermore, our investigation encompassed the exploration of the inhibitory mechanism of Al3+ ions on phase-separation structures, as well as their influence on the spectral characteristics of Re-SCGs. This work provides a new design concept for composite glass materials doped with rare-earth ions and could broaden their application in the field of high-power lasers.

Low-loss multi-mode anti-resonant hollow-core fibers.

In this work, multi-mode anti-resonant hollow-core fiber (AR-HCF) with 18 fan-shaped resonators is fabricated and characterized. The ratio of core diameter over transmitted wavelengths in the lowest transmission band is up to 85. The measured attenuation at 1 µm wavelength is below 0.1 dB/m and the bend loss below 0.2 dB/m at a bend radius smaller than 8 cm. Modal content of the multi-mode AR-HCF is characterized using the S2 imaging technique and seven LP-like modes in total are identified using a 23.6 meter fiber length. Multi-mode AR-HCFs for longer wavelengths are fabricated by scaling up the same design, extending the transmission window beyond 4 µm wavelength. Low-loss multi-mode AR-HCF could find applications in the delivery of high-power laser light with a medium beam quality, where higher coupling efficiency and laser damage threshold are expected.

Efficient three-level continuous-wave and GHz passively mode-locked laser by a Nd3+-doped silicate glass single mode fiber.

Nd3+-doped three-level (4F3/2-4I9/2) fiber lasers with wavelengths in the range of 850-950 nm are of considerable interest in applications such as bio-medical imaging and blue and ultraviolet laser generation. Although the design of a suitable fiber geometry has enhanced the laser performance by suppressing the competitive four-level (4F3/2-4I11/2) transition at ∼1 µm, efficient operation of Nd3+-doped three-level fiber lasers still remains a challenge. In this study, taking a developed Nd3+-doped silicate glass single-mode fiber as gain medium, we demonstrate efficient three-level continuous-wave lasers and passively mode-locked lasers with a gigahertz (GHz) fundamental repetition rate. The fiber is designed using the rod-in-tube method and has a core diameter of 4 µm with a numerical aperture of 0.14. In a short 4.5-cm-long Nd3+-doped silicate fiber, all-fiber CW lasing in the range of 890 to 915 nm with a signal-to-noise ratio (SNR) greater than 49 dB is achieved. Especially, the laser slope efficiency reaches 31.7% at 910 nm. Furthermore, a centimeter-scale ultrashort passively mode-locked laser cavity is constructed and ultrashort pulse at 920 nm with a highest GHz fundamental repetition is successfully demonstrated. Our results confirm that Nd3+-doped silicate fiber could be an alternative gain medium for efficient three-level laser operation.

High ytterbium concentration Yb/Al/P/Ce co-doped silica fiber for 1-µm ultra-short cavity fiber laser application.

We demonstrate a high ytterbium concentration Yb/Al/P/Ce co-doped silica fiber by conventional modified chemical vapor deposition (MCVD) technology and solution doping process. The fiber has a Yb concentration of about 2.5 wt%, and the corresponding core absorption coefficient is measured to be ∼1400 dB/m at 976 nm. The gain coefficient was measured to be approximately 1.0 dB/cm. It is found that the Yb/Al/P/Ce co-doped silica shows a lower photodarkening-induced equilibrium loss of 52 dB/m at 633 nm than the Yb/Al/P co-doped silica fiber of 117 dB/m. Using the heavily Yb3+-doped silica fiber, a compact and robust ultrashort cavity single-frequency fiber laser was achieved with a maximum output power of 75 mW and a linewidth of 14 kHz. Furthermore, a compact passively mode-locked fiber laser (MLFL) with a repetition rate of 1.23 GHz was also proposed using our developed Yb-doped fiber. The laser properties of the proposed lasers were systematically investigated, demonstrating the superior performance of this fiber in terms of photodarkening resistance and ultrashort-cavity laser application. Furthermore, utilizing an all-fiber structure based on silica-based fiber offers the significant advantage of high stability and reliability.

Brillouin gain spectrum characterization in an acoustic anti-guided delivery fiber for high power narrow linewidth laser.

The Brillouin gain spectrum (BGS) provides key information for stimulated Brillouin scattering (SBS), such as the Brillouin frequency shift (BFS), Brillouin spontaneous linewidth, and Brillouin gain coefficient. In this study, we theoretically investigate the field distributions and BGS characterization of Ge-doped, Al-doped, and Al/Ge co-doped fibers. Additionally, we analyzed and compared the relationship between the BGS and acoustic refractive index. In particular, we demonstrate the crucial role played by acoustic modes in anti-waveguide structures. The simulation results show that the Brillouin gain coefficient decreases with a decreasing acoustic index in the fiber core region. Furthermore, we experimentally measure the SBS threshold and BGS of the Al/Ge co-doped fiber to examine the validity of the numerical model. The simulated and experimental results are consistent.

Sub-kHz linewidth 1.6-µm single-frequency fiber laser based on a heavily erbium-doped silica fiber.

We present a single-frequency erbium-doped fiber laser operated at 1608.8 nm using a homemade, heavily erbium-doped silica fiber as gain medium. The laser configuration is based on a ring cavity, which is combined with a fiber saturable absorber to achieve single-frequency operation. The measured laser linewidth is less than 447 Hz and the optical signal-to-noise ratio exceeds 70 dB. The laser exhibits an excellent stability, without any instance of mode-hopping during 1-hour observing. The fluctuations in both wavelength and power were measured to be 0.002 nm and less than 0.09 dB in a 45-minutes period. The laser produces over 14 mW of output power with a slope efficiency of 5.3%, which, to the best of our knowledge, is currently the highest power directly obtained from a single-frequency cavity based on an erbium-doped silica fiber above 1.6 µm.

Extending laser wavelengths to 1630†nm in centimeter-scale Er-phosphate fiber.

The spectral bandwidth of Er-doped fibers limits their lasing wavelength at longer wave band. Here, to the best of our knowledge, we report a broad emission band (1420‒1680 nm) of Er3+ and demonstrate for the first time an Er-phosphate fiber, which supports laser oscillation at the extended wavelengths of 1627 nm and 1630 nm, with the output powers and slope efficiencies of 44 mW/12.5% and 16.5 mW/5.6%, respectively, pumped at 1480 nm. To the best of our knowledge, these are the highest output powers and slope efficiencies at 1627 nm and 1630 nm from an Er3+-doped all-fiber configuration.

Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice.

BACKGROUND: Low-carbohydrate diet (LCD) is effective for weight loss and glycaemic control in humans. Here, the study aimed to explore the effects of LCD/high-fat diet (HFD) in both humans and mice. METHODS: Twenty-two overweight or obese participants received LCD for 3 weeks. Based on carbohydrate intake > 10% or ≤ 10% of calories, the participants were divided into moderate LCD (MLCD) and very LCD (VLCD) groups. The participants completed a 10-question food preference survey. Meanwhile, C57BL/6J mice were assigned to five groups: chow diet (CD, 10% fat), HFD with 60%, 70%, and 75% fat from cocoa butter (HFD-C), and HFD with 60% fat from lard (HFD-L) and fed for 24 weeks. Eight mice were acclimatised for the food-choice test. RESULTS: LCD decreased the total energy intake in humans. The VLCD group showed greater weight loss and better glycaemic control than the MLCD group. A food preference survey showed that 65% of participants tended to choose high-carbohydrate foods. In mice, HFD resulted in energy overconsumption, obesity, and metabolic disorders. When CD and HFD-L were administered simultaneously, mice rarely consumed CD. In the HFD-C groups, the energy intake and body weight increased with increasing dietary fat content. Compared with the HFD-C group, the HFD-L group consumed more energy and had poorer metabolism. CONCLUSIONS: Lower carbohydrate intake contributed to lower energy intake and improved metabolism in humans. In mice, diets with a higher proportion of fat become more attractive and obesogenic by fixing the fat sources. Since the mice preferred lard to cocoa butter, lard induced excess energy intake and poorer metabolism. Different food preferences may be the underlying mechanism behind the opposite effects of the LCD/HFD in humans and mice. TRIAL REGISTRATION: The clinical trial was registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn ). The registration number is ChiCTR1800016786. All participants provided written informed consent prior to enrolment.

Capture of Heterogeneous Circulating Tumor Cells in Colorectal Cancer Patients on an Immunomagnetic and Anti-Nonspecific Adsorption Platform.

Circulating tumor cells (CTC) have been represented by different phenotypes due to the epithelial-mesenchymal transition (EMT), which are epithelial CTC (E-CTC), mesenchymal CTC (M-CTC), and mixed (epithelial, mesenchymal) CTC (EM-CTC). Limited work has systematically discussed the associations of CTC number, especially proportions of E-CTC, M-CTC, and EM-CTC in total CTC, with colorectal cancer (CRC) progressions via a simple method with high performances. To achieve this goal, this paper presents the fabrication of a novel anti-nonspecific adsorption immunomagnetic platform called Fe3O4@SiO2@PTMAO@Aptamer, which was obtained by modifying polymeric trimethylamine N-oxide (PTMAO) on magnetic Fe3O4@SiO2, which was then linked with dual aptamers of an epithelial cellular adhesion molecule (EpCAM) and cell surface vimentin (CSV), targeting different CTC phenotypes. Results demonstrated that the abundant coating of PTMAO on Fe3O4@SiO2 improved the anti-nonspecific adsorption and noncell adhesion abilities of the immunomagnetic particles and could capture heterogeneous CTC with higher efficiency within 10 min. These excellent performances of Fe3O4@SiO2@PTMAO@Aptamer allowed us to inspect the correlations of numbers of E-CTC, M-CTC, EM-CTC, or proportions of them in total CTC with clinical information on CRC patients in detail. Our data innovatively and clearly revealed that the captured CTC, especially M-CTC proportion, displayed more close associations with progression, diagnosis, surgery, and chemotherapeutic effects for CRC patients. Overall, we believe that our approach will bring a new understanding of CTC-based liquid biopsy for cancer diagnosis and treatment.

Temperature-Dependent Group Delay of Photonic-Bandgap Hollow-Core Fiber Tuned by Surface-Mode Coupling.

Surface modes (SM) are highly spatially localized modes existing at the core-cladding interface of photonic-bandgap hollow-core fiber (PBG-HCF). When coupling with SM, the air modes (AM) in the core would suffer a higher confinement loss despite being spectrally within the cladding photonic bandgap, and would be highly dispersive around the avoided crossing (anti-crossing) wavelength. In this paper, we numerically explored how such avoided crossings can play an important role in the tuning of the temperature dependence of group delay of AM of PBG-HCF. At higher temperatures, both the thermo-optic effect and thermal expansion contribute to the redshift of avoided crossing wavelength, giving rise to a temperature dependence of the AM dispersion. Numerical simulations show that the redshift of avoided crossing can significantly tune the thermal coefficient of delay (TCD) of PBG-HCF from -400 ps/km/K to 400 ps/km/K, approximately -120 ppm/K to 120 ppm/K. In comparison with the known tuning mechanism by thermal-induced redshift of photonic bandgap [Fokoua et al., Optica 4, 659, 2017], the tuning of TCD by SM coupling presents a much broader tuning range and higher efficiency. Our finding may provide a new route to design PBG-HCF for propagation time sensitive applications.

Improved radiation resistance of an Er-doped silica fiber by a preform pretreatment method.

We report a novel pretreatment method to improve the radiation resistance of Er-doped fiber (EDF). The processing object of this method is EDF preform, and the pretreatment processing involves three steps: deuterium loading, pre-irradiation, and thermal annealing. The effects of pretreatment conditions on the optical loss, gain performance, and radiation resistance of EDF were systematically studied. The relevant mechanisms were revealed using Fourier transform infrared (FTIR), radiation-induced absorption (RIA), and electron paramagnetic resonance (EPR) spectroscopies. The results show that the pretreatment can not only greatly reduce the hydroxyl content of the EDF core, but it can also effectively improve the radiation resistance of EDF. The online test results show that the gain of the commercial, pristine, and pretreated EDFs were reduced by 19.0, 4.2, and 1.3 dB, respectively, corresponding to a decrease of 68.1, 16.2, and 4.7% after 98 krad X-rays irradiation. The high vacuum experiments show that the pretreatment method can maintain long-term stable high radiation resistance. This work provides a reference for the development of high-performance radiation resistant EDFs for use in the lower, middle, and geosynchronous earth orbit.

Laser-induced damage of an anti-resonant hollow-core fiber for high-power laser delivery at 1 µm.

We demonstrate high-power laser delivery exceeding 1 kilowatt through a 5-meter homemade anti-resonant hollow-core fiber (AR-HCF) at 1-µm wavelength. Laser-induced damage to the fiber coating and jacket glass is experimentally observed respectively for different incident laser powers from a few hundred watts up to nearly 1.5 kilowatts. The cladding microstructure of the AR-HCF is free of damage at the incident end when 80% of the 1.5-kW incident power is coupled in. The deviation of an incident laser beam from the core to the cladding causes no damage but only deterioration of the coupling efficiency. The potential of the AR-HCF for higher-power laser delivery is discussed.

Single-cell RNA sequencing identify SDCBP in ACE2-positive bronchial epithelial cells negatively correlates with COVID-19 severity.

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in many deaths throughout the world. It is vital to identify the novel prognostic biomarkers and therapeutic targets to assist with the subsequent diagnosis and treatment plan to mitigate the expansion of COVID-19. Since angiotensin-converting enzyme 2 (ACE2)-positive cells are hosts for COVID-19, we focussed on this cell type to explore the underlying mechanisms of COVID-19. In this study, we identified that ACE2-positive cells from the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 belong to bronchial epithelial cells. Comparing with patients of COVID-19 showing severe symptoms, the antigen processing and presentation pathway was increased and 12 typical genes, HLA-DRB5, HLA-DRB1, CD74, HLA-DRA, HLA-DPA1, HLA-DQA1, HSP90AA1, HSP90AB1, HLA-DPB1, HLA-DQB1, HLA-DQA2, and HLA-DMA, particularly HLA-DPB1, were obviously up-regulated in ACE2-positive bronchial epithelial cells of patients with mild disease. We further discovered SDCBP was positively correlated with above 12 genes particularly with HLA-DPB1 in ACE2-positive bronchial epithelial cells of COVID-19 patients. Moreover, SDCBP may increase the immune infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in different lung carcinoma. Moreover, we found the expression of SDCBP was positively correlated with the expression of antigen processing and presentation genes in post-mortem lung biopsies tissues, which is consistent with previous discoveries. These results suggest that SDCBP has good potential to be further developed as a novel diagnostic and therapeutic target in the treatment of COVID-19.

The involvement of α-proteobacteria Phenylobacterium in maintaining the dominance of toxic Microcystis blooms in Lake Taihu, China.

Lake Taihu in China has suffered serious harmful cyanobacterial blooms for decades. The algal blooms threaten the ecological sustainability, drinking water safety, and human health. Although the roles of abiotic factors (such as water temperature and nutrient loading) in promoting Microcystis blooms have been well studied, the importance of biotic factors (e.g. bacterial community) in promoting and meditating Microcystis blooms remains unclear. In this study, we investigated the ecological dynamics of bacterial community, the ratio of toxic Microcystis, as well as microcystin in Lake Taihu. High-throughput 16S rRNA sequencing and principal component analysis (PCA) revealed that the bacteria community compositions (BCCs) clustered into three groups, the partitioning of which corresponded to that of groups according to the toxic profiles (the ratio of toxic Microcystis to total Microcystis, and the microcystin concentrations) of the samples. Further Spearman's correlation network showed that the α-proteobacteria Phenylobacterium strongly positively correlated with the toxic profiles. Subsequent laboratory chemostats experiments demonstrated that three Phenylobacterium strains promoted the dominance of the toxic Microcystis aeruginosa PCC7806 when co-culturing with the non-toxic PCC7806 mcyB- mutant. Taken together, our data suggested that the α-proteobacteria Phenylobacterium may play a vital role in the maintenance of toxic Microcystis dominance in Lake Taihu.

Delivery of CW laser power up to 300 watts at 1080†nm by an uncooled low-loss anti-resonant hollow-core fiber.

In this paper, we report the use of a 3-meter low-loss anti-resonant hollow-core fiber (AR-HCF) to deliver up to 300 W continuous-wave laser power at 1080 nm wavelength from a commercial fiber laser source. A near-diffraction-limited beam is measured at the output of the AR-HCF and no damage to the uncooled AR-HCF is observed for several hours of laser delivery operation. The limit of AR-HCF coupling efficiency and laser-induced thermal effects that were observed in our experiment are also discussed.