Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis.

Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.

Distributed twist sensing using frequency-scanning φ-OTDR in a spun fiber.

In this paper, a novel distributed twist sensor based on frequency-scanning phase-sensitive optical time-domain reflectometry (φ-OTDR) in a spun fiber is proposed and demonstrated. Owing to the unique helical structure of the stress rods in the spun fiber, fiber twist gives rise to the variation of the effective refractive index of the transmitting light, which can be quantitatively retrieved through frequency shift using frequency-scanning φ-OTDR. The feasibility of distributed twist sensing has been verified by both simulation and experiment. For proof of concept, distributed twist sensing over a 136 m spun fiber with a 1 m spatial resolution is demonstrated, and the measured frequency shift shows a quadratic fitting dependence on the twist angle. In addition, the responses of both clockwise and counterclockwise twist directions have also been explored and the experiment result indicates that the twist direction can be discriminated since the frequency shift directions are opposite in the correlation spectrum. The proposed twist sensor possesses some outstanding advantages, including high sensitivity, distributed twist measurement and twist direction recognition capability, etc., which is very promising for specific applications in industry, e.g., structural health monitoring, bionic robots, etc.

High-resolution liquid level sensor utilizing a microwave photonics interrogated multicore fiber interferometer.

We propose and experimentally demonstrate a high-resolution, high-sensitivity liquid level sensor based on a multicore fiber (MCF) Michelson interferometer (MI), where the sensing fiber is securely affixed to a cantilever beam, such that liquid level variations will change the beam's curvature, meanwhile leading to a substantial phase difference between the two interfering arms of the MI, and the sensor is interrogated using a microwave photonics filter (MPF) system, which can provide greatly enhanced measurement resolution compared to the traditional optical wavelength demodulation methods. The angular position of the MCF is precisely calibrated to ensure optimal sensitivity of the MI sensor. As a result, within a measurement range of up to ±14 cm, the proposed liquid level sensor achieves a sensitivity of 10.35 MHz/cm and an impressive resolution of 0.04835 cm. The proposed sensor has unique advantages of high sensitivity, superior resolution, long-term stability, etc.

Single-Cell RNA-Seq Identifies Dynamic Cardiac Transition Program from ADCs Induced by Leukemia Inhibitory Factor.

Adipose-derived cells (ADCs) from white adipose tissue are promising stem cell candidates because of their large regenerative reserves and the potential for cardiac regeneration. However, given the heterogeneity of ADC and its unsolved mechanisms of cardiac acquisition, ADC-cardiac transition efficiency remains low. In this study, we explored the heterogeneity of ADCs and the cellular kinetics of 39,432 single-cell transcriptomes along the leukemia inhibitory factor (LIF)-induced ADC-cardiac transition. We identified distinct ADC subpopulations that reacted differentially to LIF when entering the cardiomyogenic program, further demonstrating that ADC-myogenesis is time-dependent and initiates from transient changes in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. At later stages, pseudotime analysis of ADCs navigated a trajectory with 2 branches corresponding to activated myofibroblast or cardiomyocyte-like cells. Our findings offer a high-resolution dissection of ADC heterogeneity and cell fate during ADC-cardiac transition, thus providing new insights into potential cardiac stem cells.

Advances in Multicore Fiber Interferometric Sensors.

In this paper, a review of multicore fiber interferometric sensors is given. Due to the specificity of fiber structure, i.e., multiple cores integrated into only one fiber cladding, multicore fiber (MCF) interferometric sensors exhibit many desirable characteristics compared with traditional fiber interferometric sensors based on single-core fibers, such as structural and functional diversity, high integration, space-division multiplexing capacity, etc. Thanks to the unique advantages, e.g., simple fabrication, compact size, and good robustness, MCF interferometric sensors have been developed to measure various physical and chemical parameters such as temperature, strain, curvature, refractive index, vibration, flow, torsion, etc., among which the extraordinary vector-bending sensing has also been extensively studied by making use of the differential responses between different cores of MCFs. In this paper, different types of MCF interferometric sensors and recent developments are comprehensively reviewed. The basic configurations and operating principles are introduced for each interferometric structure, and, eventually, the performances of various MCF interferometric sensors for different applications are compared, including curvature sensing, vibration sensing, temperature sensing, and refractive index sensing.

COVID-19 Infection May Drive EC-like Myofibroblasts towards Myofibroblasts to Contribute to Pulmonary Fibrosis.

COVID-19 has an extensive impact on Homo sapiens globally. Patients with COVID-19 are at an increased risk of developing pulmonary fibrosis. A previous study identified that myofibroblasts could be derived from pulmonary endothelial lineage cells as an important cell source that contributes to pulmonary fibrosis. Here, we analyzed publicly available data and showed that COVID-19 infection drove endothelial lineage cells towards myofibroblasts in pulmonary fibrosis of patients with COVID-19. We also discovered a similar differentiation trajectory in mouse lungs after viral infection. The results suggest that COVID-19 infection leads to the development of pulmonary fibrosis partly through the activation of endothelial cell (EC)-like myofibroblasts.

GSK3ß Inhibition Ameliorates Atherosclerotic Calcification.

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induced ß-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3ß inhibition or endothelial-specific deletion of GSK3ß reduces atherosclerotic calcification. We also find that alterations in ß-catenin and SMAD1 induced by GSK3ß inhibition in the aortas of Apoe-/- mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp-/- mice.

GSK3ß Inhibition Reduced Vascular Calcification in Ins2Akita/+ Mice.

Endothelial-mesenchymal transition (EndMT) drives the endothelium to contribute to vascular calcification in diabetes mellitus. In our previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induces ß-catenin and reduces mothers against DPP homolog 1 (SMAD1) to direct osteoblast-like cells toward endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency. Here, we report that GSK3ß inhibition reduces vascular calcification in diabetic Ins2Akita/wt mice. Cell lineage tracing reveals that GSK3ß inhibition redirects endothelial cell (EC)-derived osteoblast-like cells back to endothelial lineage in the diabetic endothelium of Ins2Akita/wt mice. We also find that the alterations in ß-catenin and SMAD1 by GSK3ß inhibition in the aortic endothelium of diabetic Ins2Akita/wt mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in diabetic arteries through a similar mechanism to that in Mgp-/- mice.

Shaping Waves of Bone Morphogenetic Protein Inhibition During Vascular Growth.

RATIONALE: The BMPs (bone morphogenetic proteins) are essential morphogens in angiogenesis and vascular development. Disruption of BMP signaling can trigger cardiovascular diseases, such as arteriovenous malformations. OBJECTIVE: A computational model predicted that BMP4 and BMP9 and their inhibitors MGP (matrix gamma-carboxyglutamic acid [Gla] protein) and CV2 (crossveinless-2) would form a regulatory system consisting of negative feedback loops with time delays and that BMP9 would trigger oscillatory expression of the 2 inhibitors. The goal was to investigate this regulatory system in endothelial differentiation and vascular growth. METHODS AND RESULTS: Oscillations in the expression of MGP and CV2 were detected in endothelial cells in vitro, using quantitative real-time polymerase chain reaction and immunoblotting. These organized temporally downstream BMP-related activities, including expression of stalk-cell markers and cell proliferation, consistent with an integral role of BMP9 in vessel maturation. In vivo, the inhibitors were located in distinct zones in relation to the front of the expanding retinal network, as determined by immunofluorescence. Time-dependent changes of the CV2 location in the retina and the existence of an endothelial population with signs of oscillatory MGP expression in developing vasculature supported the in vitro findings. Loss of MGP or its BMP4-binding capacity disrupted the retinal vasculature, resulting in poorly formed networks, especially in the venous drainage areas, and arteriovenous malformations as determined by increased cell coverage and functional testing. CONCLUSIONS: Our results suggest a previously unknown mechanism of temporal orchestration of BMP4 and BMP9 activities that utilize the tandem actions of the extracellular antagonists MGP and CV2. Disruption of this mechanism may contribute to vascular malformations and disease.

High power 1.55 µm buried heterojunction distributed feedback laser with a linewidth less than 200 kHz.

With the rapid development of coherent optical communication systems, lasers are required to have higher power and narrower linewidths. In this paper, a process method using buried heterojunction is proposed. By comparing the optoelectronic properties of lasers with different mesa widths and different cavity lengths, the laser with a 1000 µm cavity length and a mesa width of 2.4 µm can reach 133.7 mW at 25°C at 300 mA, and a side mode suppression ratio (SMSR) greater than 50 dB. This laser also exhibits low relative intensity noise (<-150d B/H z at 260 mA) and narrow linewidth (<200k H z).

Does local vancomycin powder impregnated with autogenous bone graft and bone substitute decrease the risk of deep surgical site infection in degenerative lumbar spine fusion surgery?-An ambispective study.

BACKGROUND: Deep surgical site infection (DSSI) is one of the most challenging complications in lumbar fusion surgery. Few investigations examined the effect of vancomycin powder mixed with autogenic bone graft (ABG) and bone substitutes on preventing DSSI in degenerative lumbar fusion surgeries as well as any interference with bony fusion. The aim of the study was to investigate the effects of ABG along with bone substitutes as a local vancomycin delivery system on preventing DSSI in lumbar instrumented fusion and compared with those who did not use vancomycin powder. METHODS: From January, 2015 through December, 2015, a one-year prospective study using vancomycin powder mixed with ABG and bone substitute for degenerative lumbar fusion surgeries as vancomycin (V) group, 1 gm vancomycin for 2 and 3-level, and 2 gm for more than 3-level instrumentation. From December, 2013 through December 2014, patients received degenerative lumbar fusion surgeries without using vancomycin before the vancomycin protocol were retrospectively enrolled as non-vancomycin (NV) group. Vancomycin concentration was checked at post-operative days 1 and 3 for both the serum and drainage. Patients' demographic data, microbiology reports, fusion status and functional outcomes were evaluated. RESULTS: One hundred and ten patients were enrolled prospectively in the V group, and 86 for the NV group. After an average 41 months follow-up (range, 36-54), 3 patients (3.48%) developed postoperative DSSIs in the NV group, thereby requiring revision surgeries and parenteral antibiotics treatment versus no DSSIs (0%, 0/100) in the V group. (p = 0.048). The postoperative serum vancomycin levels were undetectable and no vancomycin related side effects was encountered. The mean vancomycin concentration of drainage at postoperative days 1 and 3 were 517.96 ± 174.4 and 220.14 ± 102.3 µg/mL, respectively. At final follow-up, there was no statistical difference observed in terms of clinical and radiologic outcomes. CONCLUSIONS: Our vancomycin protocol may reduce the incidence of DSSI in degenerative lumbar fusion surgery without affecting bony fusion. LEVEL OF EVIDENCE: Level III ambispective comparative study.

Hepatocytes derived increased SAA1 promotes intrahepatic platelet aggregation and aggravates liver inflammation in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the pathological manifestation of metabolic syndrome in liver. Its pathological changes may evolve from the initial simple steatosis to non-alcoholic steatohepatitis, liver fibrosis and even liver cancer. Numerous studies have proved that platelets play a vital role in liver disease and homeostasis. Particularly, anti-platelet therapy can reduce intrahepatic platelet aggregation and improve the inflammation of fatty liver. Previous study has also confirmed that SAA is a gene closely related to high-fat diet (HFD) induced obesity, and SAA1 can promote liver insulin resistance induced by Palmitate or HFD. Here, we found that SAA1 treated platelets presented increased sensitivity of platelet aggregation, enhanced activation and increased adhesion ability, and such function was partly dependent on Toll-Like Receptor (TLR) 2 signaling. In addition, blocking SAA1 expression in vivo not only inhibited platelet aggregation in the liver tissues of NAFLD mice, but also alleviated the inflammation of fatty liver. In conclusion, our findings identify that HFD-induced hepatic overexpressed SAA1 aggravates fatty liver inflammation by promoting intrahepatic platelet aggregation, these results also imply that SAA1 may serve as a potential target for ameliorating NAFLD.

Postoperative spinal orthosis may not be necessary for minimally invasive lumbar spine fusion surgery: a prospective randomized controlled trial.

BACKGROUND: With the progress and success in minimally invasive surgery of transforaminal lumbar interbody fusion (MIS TLIF), the musculoskeletal injury was minimized. However, the role of postoperative orthosis in MIS TLIF has not been established and there is little evidence supporting the routine use of orthosis in MIS TLIF. METHODS: This is a prospective randomized clinical study. 90 patients who underwent MIS TLIF were randomly divided into groups A (with postoperative spinal orthosis) and B (without postoperative spinal orthosis). Patients were followed up for an average of 12.6 months. Clinical outcome was assessed using the Oswestry disability index (ODI) and visual analogue scale (VAS). Fusion rate was classified with the BSF scale system at postoperative 6-month, and 12-month. RESULTS: Both groups had similar patient demographics. The use of postoperative spinal orthosis had no significant influence on instrumentation-related complications or radiological parameters at each follow-up. CONCLUSIONS: In this study, we conclude that postoperative spinal orthosis is not necessary for MIS TLIF. Patients without postoperative spinal orthosis had the same fusion rates and improvement of VAS and ODI scores.

Differences in the interbody bone graft area and fusion rate between minimally invasive and traditional open transforaminal lumbar interbody fusion: a retrospective short-term image analysis.

PURPOSE: We aimed to quantify the interbody bone graft area following transforaminal lumbar interbody fusion (TLIF) using traditional open and minimally invasive surgeries (MIS) and investigate their correlations with rates of fusion, complications, and clinical outcomes. METHODS: Patients undergoing TLIF of 1 or 2 levels between October 2015 and December 2016 were retrospectively included. Fusion and bone graft areas were assessed with computed tomography (CT) at 6 months postoperatively. The bone graft area ratio was defined as the bone graft area divided by the average endplate area. The distributions of bone graft area within the discs were also recorded. Clinical outcomes were assessed using the visual analog scale (VAS) and Oswestry Disability Index (ODI) questionnaires. RESULTS: In total, 77 disc levels in 57 patients were analyzed. The fusion rate was 79.1% in the open group and 82.4% in the MIS group (p = 0.718). Clinical outcomes of both groups improved significantly. Changes in VAS and ODI scores at 12 months postoperatively were comparable between groups. Bone graft area ratio was not significantly different between the two groups (open, 38 ± 10.8%; MIS, 38.1 ± 9.0%, p = 0.977). Analysis of bone graft distribution revealed that the contralateral-dorsal part of the disc had the lowest bone graft area. The bone graft area ratio was significantly higher in the solid union group (39.2 ± 10.4%) than in the non-solid union group (33.5 ± 6.4%, p = 0.048). CONCLUSIONS: The fusion rates, bone graft area ratios, clinical outcomes, and complications were similar between MIS and open TLIF. These slides can be retrieved under Electronic Supplementary Material.

What is the difference in morphologic features of the lumbar vertebrae between Caucasian and Taiwanese subjects? A CT-based study: implications of pedicle screw placement via Roy-Camille or Weinstein method.

BACKGROUND: Safe placement of pedicle screws without jeopardizing neurovascular structures medially and anteriorly is important during spine surgery. Inferior breach of pedicle is also dangerous due to low margin of error. Lumbar morphology and identical pedicle orientation at L1 to L5 shown on CT scan of young Taiwanese patients (90 patients) were analyzed and compared with findings reported for Caucasian subjects. METHODS: Previously reported techniques were employed to quantitatively elucidate the parameters regarding lumbar morphology and identical pedicle orientation at each vertebra. The parameters for pedicle angle (PA), pedicle diameter (PD), pedicle axis distance (PAD), midline axis distance (MAD), transverse pedicle axis distance (TPAD) and transverse intertangential angle (TITA) were measured. RESULTS: Taiwanese subjects had different PA, PD, PAD, MAD at L1 to L5 and TITA at L3 to L5 compared with Caucasian subjects. L5 had the most convergent pedicle axis, the widest PD and the shortest antero-posterior axis morphology. CONCLUSIONS: This study provides detailed information for identifying pedicle orientation during pedicle screw placement and elucidate racial differences in lumbar morphology and pedicle orientation between Taiwanese and Caucasian populations.

Combined effects of bone morphogenetic protein 10 and crossveinless-2 on cardiomyocyte differentiation in mouse adipocyte-derived stem cells.

Bone morphogenetic protein (BMP) 10, a cardiac-restricted BMP family member, is essential in cardiomyogenesis, especially during trabeculation. Crossveinless-2 (CV2, also known as BMP endothelial cell precursor derived regulator [BMPER]) is a BMP-binding protein that modulates the activity of several BMPs. The objective of this study was to examine the combined effects of BMP10 and CV2 on cardiomyocyte differentiation using mouse dedifferentiated fat (mDFAT) cells, which spontaneously differentiate into cardiomyocyte-like cells, as a model. Our results revealed that CV2 binds directly to BMP10, as determined by co-immunoprecipitation, and inhibits BMP10 from initiating SMAD signaling, as determined by luciferase reporter gene assays. BMP10 treatment induced mDFAT cell proliferation, whereas CV2 modulated the BMP10-induced proliferation. Differentiation of cardiomyocyte-like cells proceeded in a reproducible fashion in mDFAT cells, starting with small round Nkx2.5-positive progenitor cells that progressively formed myotubes of increasing length that assembled into beating colonies and stained strongly for Troponin I and sarcomeric alpha-actinin. BMP10 enhanced proliferation of the small progenitor cells, thereby securing sufficient numbers to support formation of myotubes. CV2, on the other hand, enhanced formation and maturation of large myotubes and myotube-colonies and was expressed by endothelial-like cells in the mDFAT cultures. Thus BMP10 and CV2 have important roles in coordinating cardiomyogenesis in progenitor cells.

Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.

RATIONALE: Endothelial cells have the ability to undergo endothelial-mesenchymal transitions (EndMTs), by which they acquire a mesenchymal phenotype and stem cell-like characteristics. We previously found that EndMTs occurred in the endothelium deficient in matrix γ-carboxyglutamic acid protein enabling endothelial cells to contribute cells to vascular calcification. However, the mechanism responsible for initiating EndMTs is not fully understood. OBJECTIVE: To determine the role of specific serine proteases and sex determining region Y-box 2 (Sox2) in the initiation of EndMTs. METHODS AND RESULTS: In this study, we used in vivo and in vitro models of vascular calcification to demonstrate that serine proteases and Sox2 are essential for the initiation of EndMTs in matrix γ-carboxyglutamic acid protein-deficient endothelium. We showed that expression of a group of specific serine proteases was highly induced in endothelial cells at sites of vascular calcification in Mgp null aortas. Treatment with serine protease inhibitors decreased both stem cell marker expression and vascular calcification. In human aortic endothelial cells, this group of serine proteases also induced EndMTs, and the activation of proteases was mediated by Sox2. Knockdown of the serine proteases or Sox2 diminished EndMTs and calcification. Endothelial-specific deletion of Sox2 decreased expression of stem cell markers and aortic calcification in matrix γ-carboxyglutamic acid protein-deficient mice. CONCLUSIONS: Our results suggest that Sox2-mediated activation of specific serine proteases is essential for initiating EndMTs, and thus, may provide new therapeutic targets for treating vascular calcification.