Sensitivity enhancement of bimodal waveguide interferometric sensor based on regional mode engineering.

In this paper, we propose a novel bimodal waveguide based on regional mode engineering (BiMW-RME). Leveraging the orthogonality of the guided modes, the form of patterned SiO2 cladding on the bimodal waveguide can reduce the interaction between the reference mode and the analyte, thereby significantly improving sensitivity. The proposed BiMW-RME sensor experimentally demonstrates a phase sensitivity of 2766 π rad/RIU/cm and a detection limit of 2.44×1-5 RIU. The sensitivity is 2.7 times higher than that of the conventional BiMW sensor on the same SOI platform. The proposed design strategy demonstrates a significant improvement in the sensor's sensitivity, presenting a novel approach to enhancing common-path interferometric sensor performance.

On-Chip Fabrication-Tolerant Exceptional Points Based on Dual-Scatterer Engineering.

The intriguing and anomalous optical characteristics of exceptional points (EPs) in optical resonators have attracted significant attention. While EP-related phenomena have been observed by perturbing resonators with off-chip components, implementing EPs fully on-chip remains challenging due to their extreme susceptibility to fabrication errors. In this Letter, we propose a succinct and compact approach to reach EP in an on-chip integrated silicon microring resonator by manipulating the evolution of backscatterings with two nanocylinders of disparate diameters. The theoretical analysis unveils that the fabrication constraints could be significantly relieved by increasing the difference in diameters of the nanocylinders. The evolution from non-EP to EP is traced experimentally through the step-by-step tuning of the angular and radial positions of nanocylinders. The proposed method opens a pathway toward the on-chip high-density integration of non-Hermitian devices.

Ultrasensitive fiber sensor with enhanced Vernier effect for simultaneous measurements of transverse load and temperature.

Based on enhanced Vernier effect, a compact fiber sensor with ultrahigh sensitivity is proposed for simultaneous transverse load (TL) and temperature measurements. A single mode fiber (SMF) is spliced with a segment of hollow-core fiber (HCF) coated with polydimethylsiloxane (PDMS), some PDMS is injected into the HCF, forming a Vernier sensor with an air cavity adjacent to a PDMS cavity. It is shown that TL and temperature changes give rise to opposite and remarkable different variations in lengths of the two cavities, thereby enhancing Vernier effect and in favor of simultaneous measurements of TL and temperature. Moreover, the limited sensitivity magnification due to the length mismatch between the two cavities is compensated for by reconstructing the Vernier envelope with a broadened free spectrum range (FSR) from output signal. As a result, the highest TL sensitivity reported so far of -2637.47 nm/N and a good condition number of 69.056 for the sensitivity coefficient matrix have been achieved.

Composite Fabry-Perot interferometric gas pressure and temperature sensor utilizing four hole fiber with sensitivity boosted by high-order harmonic Vernier effect.

It is an enormous challenge for optical fiber sensors to intuitively achieve the simultaneous measurement of both gas pressure and temperature with high sensitivity. To address this challenge, the Fabry-Perot interferometer (FPI) based on high-order harmonic Vernier effect is combined with the fiber Bragg grating (FBG). A novel fiber sensor built with a cascaded FPI and an FBG for the simultaneous measurement of gas pressure and temperature is designed and experimentally investigated by virtue of the temperature sensing property of FBG and its independence on gas pressure-induced refractive index change, where a high-order harmonic Vernier effect was utilized to boost the gas pressure sensitivity of the sensor. As gas pressure increases from 0 to 1 MPa, the internal envelope of composite FBG and FPI based 10-order harmonic Vernier effect exhibits redshift with maximal sensitivities of 146.64 nm/MPa and a high magnification factor of 43. FBG is insensitive to gas pressure change, whereas, the spectral response of the internal envelope 10-order harmonic Vernier effect and FBG monotonously move and undergo blueshift and redshift as the temperature increases from 30 °C to 120 °C with maximal sensitivities of -0.48 and 0.011 nm/°C, respectively. Therefore, the distinct sensitivities of FBG and FPI to gas pressure and temperature result in extraction of both gas pressure and temperature information simultaneously by constructing measurement matrixes.

Slab control on the mega-sized North Pacific ultra-low velocity zone.

Ultra-low velocity zones (ULVZs) are localized small-scale patches with extreme physical properties at the core-mantle boundary that often gather at the margins of Large Low Velocity Provinces (LLVPs). Recent studies have discovered several mega-sized ULVZs with a lateral dimension of ~900 km. However, the detailed structures and physical properties of these ULVZs and their relationship to LLVP edges are not well constrained and their formation mechanisms are poorly understood. Here, we break the degeneracy between the size and velocity perturbation of a ULVZ using two orthogonal seismic ray paths, and thereby discover a mega-sized ULVZ at the northern edge of the Pacific LLVP. The ULVZ is almost double the size of a previously imaged ULVZ in this region, but with half of the shear velocity reduction. This mega-sized ULVZ has accumulated due to stable mantle flow converging at the LLVP edge driven by slab-debris in the lower mantle. Such flow also develops the subvertical north-tilting edge of the Pacific LLVP.

Association Between Serum Galectin-3 Levels and Coronary Stenosis Severity in Patients With Coronary Artery Disease.

BACKGROUND: The relationship between galectin-3 (Gal-3) and coronary artery disease (CAD) has not been fully elucidated. AIM: This study aimed to determine the relationship between the presence and severity of CAD and serum Gal-3 levels. PATIENTS AND METHODS: Three-hundred thirty-one consecutive CAD patients were enrolled as the study group. An additional 62 patients without CAD were enrolled as the control group. Serum Gal-3 levels were separately compared between the non-CAD and CAD groups, among the stable CAD and Acute coronary syndrome (ACS) groups, and between CAD patients with low and high SYNTAX scores (SSs). The 1-year cumulative rate of major adverse cardiac events (MACEs) was also compared among ACS patients by Gal-3 levels. RESULTS: Serum Gal-3 was significantly higher in the CAD group than in the non-CAD group 3.89 (0.16-63.67) vs. 2.07 (0.23-9.38) ng/ml, P < 0.001. Furthermore, serum Gal-3 was significantly higher in the non-ST-segment elevation ACS (NSTE-ACS) group than that in the stable CAD group, 4.72 (1.0-16.14) vs. 2.23 (0.65-23.8) ng/ml, P = 0.04 and higher in the ST-segment elevation myocardial infarction (STEMI) group than that in the stable CAD group 7.87 (0.59-63.67) vs. 2.23 (0.65-23.8) ng/ml, P < 0.001. Serum Gal-3 level was an independent predictor of ACS compared with stable CAD group (OR = 1.131, 95% CI: 1.051-1.217, P = 0.001) as well as high SS (OR = 1.030, 95% CI: 1.021-1.047, P = 0.038) after adjust other confounding risk factors. Acute coronary syndrome patients with Gal-3 levels above the median (gal-3 = 4.78 ng/ml) showed a higher cumulative MACE rate than those with Gal-3 levels below the median. After adjusting other confounding risk factors, Gal-3 remained an independent risk factor for the cumulative rate of MACEs in ACS patients (6% higher rate of MACEs incidence per 1 ng/ml increment of Gal-3). CONCLUSION: Galectin-3 correlated with the presence of CAD as well as coronary stability and complexity. Galectin-3 may be valuable in predicting mid-term prognosis in ACS patients.

Structure-Based Design and Synthesis of N-Substituted 3-Amino-ß-Carboline Derivatives as Potent αß-Tubulin Degradation Agents.

So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting αß-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of 2 were designed and synthesized based on 2-tubulin cocrystal structure. Among them, 12b displayed nanomolar potency against a variety of tumor cells, including paclitaxel- and adriamycin-resistant cell lines. 12b binds to the colchicine site and promotes αß-tubulin degradation in a concentration-dependent manner via the ubiquitin-proteasome pathway. The X-ray crystal structure revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring, which resulted in better interaction of 12b with surrounding residues. 12b effectively suppressed tumor growth at an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive) and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective TGIs of 92.42 and 79.75% without obvious side effects, supporting its potential utility as a tumor-therapeutic compound.

Association Between Fasting Hyperglycemia and New-Onset Atrial Fibrillation in Patients With Acute Myocardial Infarction and the Impact on Short- and Long-Term Prognosis.

Background: The relationship between fasting hyperglycemia (FHG) and new-onset atrial fibrillation (AF) in patients with acute myocardial infarction (AMI) is unclear, and whether their co-occurrence is associated with a worse in-hospital and long-term prognosis than FHG or AF alone is unknown. Objective: To explore the correlation between FHG and new-onset AF in patients with AMI, and their impact on in-hospital and long-term all-cause mortality. Methods: We performed a retrospective cohort study comprising 563 AMI patients. The patients were divided into the FHG group and the NFHG group. The incidence of new-onset AF during hospitalization was compared between the two groups and sub-groups under different Killip grades. Logistic regression was used to assess the association between FHG and new-onset AF. In-hospital mortality and long-term all-cause mortality were compared among patients with FHG, AF, and with both FHG and AF according to 10 years of follow-up information. Results: New-onset AF occurred more frequently in the FHG group than in the NFHG group (21.6 vs. 9.2%, p < 0.001). This trend was observed for Killip grade I (16.6 vs. 6.5%, p = 0.002) and Grade II (17.1 vs. 6.9%, p = 0.005), but not for Killip grade III-IV (40 vs. 33.3%, p = 0.761). Logistic regression showed FHG independently correlated with new-onset AF (OR, 2.56; 95% CI, 1.53-4.30; P < 0.001), and 1 mmol/L increased in fasting glucose was associated with a 5% higher rate of new-onset AF, after adjustment for traditional AF risk factors. AMI patients complicated with both fasting hyperglycemia and AF showed the highest in-hospital mortality and long-term all-cause mortality during an average of 11.2 years of follow-up. Multivariate Cox regression showed FHG combined with AF independently correlated with long-term all-cause mortality after adjustment for other traditional risk factors (OR = 3.13, 95% CI 1.64-5.96, p = 0.001), compared with the group with neither FHG nor new-onset AF. Conclusion: FHG was an independent risk factor for new-onset AF in patients with AMI. AMI patients complicated with both FHG and new-onset AF showed worse in-hospital and long-term all-cause mortality than with FHG or AF alone.

Signal processing assisted Vernier effect in a single interferometer for sensitivity magnification.

The Vernier effect magnifies optical sensitivity by the superposition of two spectra with slightly shifted frequencies from a sensing interferometer (SIM) and a reference interferometer (RIM). In this study, we demonstrate that the Vernier effect can be obtained through a single interferometer, which detects the changed signal and provides an artificial reference spectrum (ARS) to be superposed with the changed signal spectrum. The ARS extracted by spatial frequency down-conversion of one sensing spectrum in the signal processing is not affected by environmental changes and can be detuned at an arbitrarily small amount with the measured signal spectrum. This approach is simpler and accurate and provides ultrahigh sensitivity. To validate the principle, a Mach-Zehnder (MZ) interferometer based on a dual-mode microfiber was designed for sensing the refractive index (RI) change magnification, and a high sensitivity of 71354.58 nm/refractive index unit (RIU) was obtained with good linearity.

Subwavelength structure enabled ultra-long waveguide grating antenna.

Because of the high index contrast, current silicon photonics based optical phased arrays cannot achieve small beam divergence and large field-of-view simultaneously without increasing fabrication complexity. To resolve the dilemma, we propose an ultra-long waveguide grating antenna formed by placing subwavelength segments within the evanescent field of a conventional strip waveguide. Bound state in the continuum effect is leveraged to suppress the sidewall emission. As a proof of concept, we theoretically demonstrated a millimeter-long through-etched waveguide grating antenna with a divergence angle of 0.081° and a feature size compatible with current silicon photonics foundries.

Differentiation of Glioma Mimicking Encephalitis and Encephalitis Using Multiparametric MR-Based Deep Learning.

BACKGROUND: Computational aid for diagnosis based on convolutional neural network (CNN) is promising to improve clinical diagnostic performance. Therefore, we applied pretrained CNN models in multiparametric magnetic resonance (MR) images to classify glioma mimicking encephalitis and encephalitis. METHODS: A data set containing 3064 MRI brain images from 164 patients with a final diagnosis of glioma (n = 56) and encephalitis (n = 108) patients and divided into training and testing sets. We applied three MRI modalities [fluid attenuated inversion recovery (FLAIR), contrast enhanced-T1 weighted imaging (CE-T1WI) and T2 weighted imaging (T2WI)] as the input data to build three pretrained deep CNN models (Alexnet, ResNet-50, and Inception-v3), and then compared their classification performance with radiologists' diagnostic performance. These models were evaluated by using the area under the receiver operator characteristic curve (AUC) of a five-fold cross-validation and the accuracy, sensitivity, specificity were analyzed. RESULTS: The three pretrained CNN models all had AUC values over 0.9 with excellent performance. The highest classification accuracy of 97.57% was achieved by the Inception-v3 model based on the T2WI data. In addition, Inception-v3 performed statistically significantly better than the Alexnet architecture (p<0.05). For Inception-v3 and ResNet-50 models, T2WI offered the highest accuracy, followed by CE-T1WI and FLAIR. The performance of Inception-v3 and ResNet-50 had a significant difference with radiologists (p<0.05), but there was no significant difference between the results of the Alexnet and those of a more experienced radiologist (p >0.05). CONCLUSIONS: The pretrained CNN models can automatically and accurately classify these two diseases and further help to improving clinical diagnostic performance.

N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms.

In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the superior derivative 13ac. Compound 13ac showed excellent potency on JAK2 kinase, SET-2, and Ba/F3V617F cells (high expression of JAK2V617F mutation) with IC50 values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound 13ac could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound 13ac also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, 13ac significantly ameliorated the disease symptoms in a Ba/F3-JAK2V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.

The potential influence of stochastic resonance vibrations on neuromuscular strategies and center of pressure sway during single-leg stance.

BACKGROUND: Stochastic resonance vibrations are known to enhance balance in the elderly and patients with impaired plantar sensation. However, the underlying mechanisms of plantar vibrations on balance capacity are not well resolved. This study investigated the impact of stochastic resonance vibrations on activities of major extrinsic foot muscles and center of pressure sway in tactile inhibited subjects. METHODS: Using a customized vibration insole, single-leg stance tests were performed in fourteen healthy subjects at control, ice-intervention-only (inhibited foot sensation) and ice-intervention plus vibration conditions. The sway parameters and the root mean square of electromyography of medial gastrocnemius, tibialis anterior, peroneus longus, and extensor digitorum longus were examined. FINDINGS: The sway area in the ice-intervention-only condition was significantly increased compared with the control (P < .001). Following vibrations, the sway area, however, was significantly decreased. Regression analysis showed the activity levels of all extrinsic foot muscles were positively correlated with sway area when foot sensation was inhibited. In contrast, following vibrations, only that of the tibialis anterior muscle was positively correlated with sway area, indicative of a muscle control strategy similar to the control condition. INTERPRETATION: The study showed that stochastic resonance vibrations could effectively reduce body sway in the healthy subjects with inhibited foot sensation. The effects seemed to be associated with improved muscle activities in particular to the tibialis anterior muscle. It suggested that vibration insole may be used as a means to affect neuromuscular strategies to enhance balance control in people with diminished plantar sensations.

Ultrasensitive refractive index sensor based on enhanced Vernier effect through cascaded fiber core-offset pairs.

An ultrasensitive refractive index (RI) sensor based on enhanced Vernier effect is proposed, which consists of two cascaded fiber core-offset pairs. One pair functions as a Mach-Zehnder interferometer (MZI), the other with larger core offset as a low-finesse Fabry-Perot interferometer (FPI). In traditional Vernier-effect based sensors, an interferometer insensitive to environment change is used as sensing reference. Here in the proposed sensor, interference fringes of the MZI and the FPI shift to opposite directions as ambient RI varies, and to the same direction as surrounding temperature changes. Thus, the envelope of superimposed fringe manifests enhanced Vernier effect for RI sensing while reduced Vernier effect for temperature change. As a result, an ultra-high RI sensitivity of -87261.06 nm/RIU is obtained near the RI of 1.33 with good linearity, while the temperature sensitivity is as low as 204.7 pm/ °C. The proposed structure is robust and of low cost. Furthermore, the proposed scheme of enhanced Vernier effect provides a new perspective and idea in other sensing field.

Embryonic and postnatal tendon cells respond differently to interleukin-1ß.

Adult tendons heal as scar tissue, whereas embryonic tendons heal scarlessly via unknown mechanisms. Scarred tendon healing results from inflammation-driven imbalances in anabolic and catabolic functions. To test scarless versus scarring age tendon cell responses to inflammatory conditions, we treated embryonic and postnatal tendon cells with interleukin (IL)-1ß and characterized expression of collagens, matrix metalloproteinases (MMPs), inflammatory mediators, and phosphorylation of signaling molecules. At baseline, postnatal cells expressed significantly higher levels of inflammatory mediators. When treated with IL-1ß, both postnatal and embryonic cells upregulated inflammatory mediators and MMPs. Notably, postnatal cells secreted inflammatory factors up to 12.5 times the concentration in embryonic cultures. IL-1ß activated NF-κB p65 and p38 mitogen-activated protein kinase (MAPK) pathways in both cell types, but phosphorylated p38 MAPK levels were two times higher in postnatal than embryonic cells. Our results suggest that scarred healing tendon cells respond to proinflammatory cytokines by promoting an imbalance in anabolic and catabolic functions, and that the heightened response involves p38 MAPK signaling activity. In contrast, embryonic cell responses are smaller in magnitude. These intriguing findings support a potential role for tendon cells in determining scarless versus scarred healing outcomes by regulating the balance between anabolic and catabolic functions during tendon healing.

Roadmap of molecular, compositional, and functional markers during embryonic tendon development.

Tendon is a specialized connective tissue that connects muscle to bone, thereby enabling musculoskeletal movement. Tendon injury leads to formation of tissue with aberrant functional properties. Current approaches to treat tendon injuries, including surgical repair and tissue engineering, have not achieved normal tendon. A roadmap of markers could help with identifying when mis-steps occur during aberrant tendon formation and providing instructions for normal tendon formation. We propose this roadmap should be based on the embryo-the perfect model of tissue formation. Our prior studies have shown that adult mesenchymal stem cells mimic tendon progenitor cell behavior when treated with tendon developmental cues. Although transcription factors and extracellular matrix molecules are commonly used to assess tendon development, we have shown that these markers do not reliably reflect functional property elaboration. Thus, evaluating tendon formation on the basis of a combination of these molecular, compositional, and functional markers is important. In this review, we highlight various tendon markers with focus on their temporal profiles and roles in tendon development to outline a roadmap that may be useful for informing tendon healing and tissue engineering strategies.

Embryo movements regulate tendon mechanical property development.

Tendons transmit forces from muscles to bones to enable skeletal motility. During development, tendons begin to bear load at the onset of embryo movements. Using the chick embryo model, this study showed that altered embryo movement frequency led to changes in elastic modulus of calcaneal tendon. In particular, paralysis led to decreased modulus, whereas hypermotility led to increased modulus. Paralysis also led to reductions in activity levels of lysyl oxidase (LOX), an enzyme that we previously showed is required for cross-linking-mediated elaboration of tendon mechanical properties. Additionally, inhibition of LOX activity abrogated hypermotility-induced increases in modulus. Taken together, our findings suggest embryo movements are critical for tendon mechanical property development and implicate LOX in this process. These exciting findings expand current knowledge of how functional tendons form during development and could guide future clinical approaches to treat tendon defects associated with abnormal mechanical loading in uteroThis article is part of the Theo Murphy meeting issue 'Mechanics of development'.

Metformin Inhibits Mouse Islet Insulin Secretion and Alters Intracellular Calcium in a Concentration-Dependent and Duration-Dependent Manner near the Circulating Range.

Metformin is considered the first-line treatment for type 2 diabetes. While metformin primarily increases insulin sensitivity, evidence also suggests that metformin affects the activity of insulin-secreting pancreatic islets. This study was designed to systematically examine the direct effects of metformin by measuring insulin secretion and the kinetics of the calcium response to glucose stimulation in isolated mouse islets using varying concentrations (20 µM, 200 µM, and 1 mM) and durations (~1, 2, and 3 days) of metformin exposure. We observed both concentration- and duration-dependent inhibitory effects of metformin. Concentrations as little as 20 µM (nearing circulating therapeutic levels) were sufficient to reduce insulin secretion following 3-day treatment. Concentrations of 200 µM and 1 mM produced more pronounced effects more rapidly. With 1 mM metformin, islets showed severe impairments in calcium handling, inhibition of insulin secretion, and increased cell death. No stimulatory effects of metformin were observed for any experimental endpoint. We conclude that the direct effects of metformin on islets are inhibitory at near-physiological concentrations. Beneficial effects of metformin observed on islets under various stressors may occur by "resting" fatigued cellular processes. However, metformin may have unintended consequences on normally functioning islets within the circulating range that require further evaluation.