Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology.

BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.

Mitochondria complex I deficiency in Candida albicans arrests the cell cycle at S phase through suppressive TOR and PKA pathways.

How mutations in mitochondrial electron transport chain (ETC) proteins impact the cell cycle of Candida albicans was investigated in this study. Using genetic null mutants targeting ETC complexes I (CI), III (CIII), and IV (CIV), the cell cycle stages (G0/G1, S phase, and G2/M) were analyzed via fluorescence-activated cell sorting (FACS). Four CI null mutants exhibited distinct alterations, including extended S phase, shortened G2/M population, and a reduction in cells size exceeding 10 µM. Conversely, CIII mutants showed an increased population in G1/G0 phase. Among four CI mutants, ndh51Δ/Δ and goa1Δ/Δ displayed aberrant cell cycle patterns correlated with previously reported cAMP/PKA downregulation. Specifically, nuo1Δ/Δ and nuo2Δ/Δ mutants exhibited increased transcription of RIM15, a central hub linking cell cycle with nutrient-dependent TOR1 and cAMP/PKA pathways and Snf1 aging pathway. These findings suggest that suppression of TOR1 and cAMP/PKA pathways or enhanced Snf1 disrupts cell cycle progression, influencing cell longevity and growth among CI mutants. Overall, our study highlights the intricate interplay between mitochondrial ETC, cell cycle, and signaling pathways.

High-performance temperature and pressure dual-parameter sensor based on a polymer-coated tapered optical fiber.

Based on the polymer encapsulation method, a compact structure and high-sensitivity temperature and pressure dual parametric sensor was developed in this paper by wrapping an optical microfiber coupler (OMC) in polydimethylsiloxane (PDMS). Benefiting from the stable chemical properties and good optical field control ability of PDMS, the sensor showed good stability and repeatability. The dependence of the sensor sensitivity on wavelength, temperature, and pressure was experimentally investigated. The results showed that the temperature and pressure sensitivity could reach -2.283 nm/°C and 3.301 nm/Mpa in the C-band range. To overcome the cross-sensitivity of sensor temperature and pressure, a sensitivity matrix was established to realize dual-parameter simultaneous demodulation. In addition, the pressure repeatability of the sensor was tested. Based on this, the sensitivity matrix was further calibrated to reduce the error and improve the accuracy of demodulation. Finally, we also designed a protective shell for the sensor to meet the requirements of practical marine applications. Compared with other existing types of optical fiber sensors, this sensor has the advantages of simple fabrication, high sensitivity, and environmental adaptability, and has great potential for application in the field of marine environmental monitoring.

Design of photonic crystal fiber to excite surface plasmon resonance for highly sensitive magnetic field sensing.

To improve the sensing performance of optical fiber magnetic field sensor based on magneto-refractive effect, a D-shaped photonic crystal fiber-surface plasmon resonance (PCF-SPR) sensor based on magneto-refractive effect is proposed and its magnetic field sensing characteristics are investigated. The designed D-shaped PCF has a core-analyte-gold structure. Within the D-shaped PCF, the side polishing surface is coated with the gold film and the special hole is sandwiched between the core and the gold film. To realize the high magnetic field sensitivity for the fiber SPR magnetic field sensor, the special hole is filled with magnetic fluid (MF). In this paper, we analyze the mode transmission characteristics and magnetic field sensing characteristics of this fiber sensor by finite element method. We also obtain a general rule for the optimization of PCF-SPR sensors by analyzing the dispersion curves, the energy of the surface plasmon polariton mode and the core mode on the sensing performance of the designed fiber sensor. The maximum refractive index sensitivity and magnetic field sensitivity of the optimized fiber are 59714.3 nm/RIU and 21750 pm/mT (50-130 Oe), respectively. Compared with optical fiber magnetic field sensors based on magneto-refractive effect reported previously, the magnetic field sensitivity in this paper is nearly two orders of magnitude higher and it can initially achieve nT magnitude magnetic field resolution and testing capability. The proposed fiber sensor has the advantages of simple structure, easy production, high sensitivity, and strong environmental adaptability. It not only improves the sensing performance of optical fiber magnetic field sensors, but also provides an ideal alternative platform for biosensors like microfluidics because of its high refractive index sensitivity and the special structure.

Directivity Dependence of a Distributed Fiber Optic Hydrophone on Array Structure.

A distributed fiber optic hydrophone (DFOH) is a new type of fiber optic hydrophone (FOH) with adjustable structure. The dependence of the directivity of a DFOH on array structure is theoretically and experimentally studied. The directivity function of a sensing channel and that of a DFOH are derived. Based on the directivity function, the simulations are performed. Finally, the theoretical analysis is demonstrated by the experiments performed on Qingyang lake, and the results reveal that the longer sensing channel length guarantees the lower first-order side lobe and the narrower main lobe. As the channel length increased from 1 to 3, the main lobe width and first-order side lobe height decreased by 4.9° and 6 dB, respectively. In addition, channel spacing is irrelevant to directivity as the spacing is shorter than the wavelength. As the channel spacing increased from 0 to 1, the variations of the main lobe width and first-order side lobe height are lower than 0.5° and 0.94 dB, respectively. This study would provide guidance for the structure design of a distributed fiber optic hydrophone in signal processing.

Suppression of Modulation Instability Induced Phase Noise in the Long-Haul Phase-Sensitive Optical Time Domain Reflectometry.

Modulation instability (MI) is the main limitation factor of the maximum optical power in long-haul phase-sensitive optical time domain reflectometry (Φ-OTDR), and induces signal fading and serious phase noise. In this paper, a method of coherent seed injection is proposed to suppress the MI-induced phase noise in long-haul Φ-OTDR. The spontaneous MI is suppressed by stimulating induced MI in an optical fiber. The visibility of the signal in Φ-OTDR is enhanced and the phase noise is suppressed significantly. This paper offers an effective method to increase the maximum input power with the MI-induced phase noise suppressed in the long-haul Φ-OTDR system. As a result, the maximum input power and sensing distance can be potentially increased, which is greatly beneficial to the enhancement of the performance of long-haul Φ-OTDR.

The Two-Stage Suspension System of the Fiber Optic Vector Hydrophone for Isolating the Vibration from the Mooring Rope.

The two-stage suspension system (TSSS) is designed for the fiber optic vector hydrophone (FOVH) to isolate the vibration from the mooring rope. The acceleration transmissibility of the TSSS is studied theoretically and experimentally. The results show that the TSSS has a major advantage over the traditional one-stage suspension system (OSSS). Typically, the vibration isolation of the TSSS is demonstrated to be over 25 dB higher than that of the OSSS at 100 Hz. Meanwhile, it is demonstrated that the TSSS has little negative influence on the in-band acceleration response of the FOVH. The TSSS has the prospect of reducing the mechanical noise of the FOVH, which is conducive to suppressing the self-noise and enhancing the ability of weak signal detection.

Magnetic field and temperature two-parameter sensor based on optical microfiber coupler interference (OMCI) wrapped with magnetic fluid and PDMS.

In this paper, an optical fiber magnetic field and temperature sensor based on an optical microfiber coupler (OMC), Polydimethylsiloxane (PDMS), and magnetic fluid (MF) is proposed, and its magnetic field and temperature sensing characteristics are analyzed theoretically and verified experimentally. Based on the OMC and using MF as the sensing medium, the sensor can respond to the magnetic field and temperature respectively after encapsulated by PDMS. The experimental results show that the maximum magnetic field sensitivity is 96.8 pm/Oe, and the maximum temperature sensitivity is 919.1 pm/°C. To overcome the cross-sensitivity of the magnetic field and temperature of the sensor, the sensitivity matrix is established and demodulated. In addition, we discuss the optimization of the sensitivity demodulation matrix by the size design of the PDMS package and the OMC structure. The proposed two-parameter sensor in this article has the advantages of high sensitivity, low cost, small volume and high integration, which is of great significance for the multi-parameter sensing of basic physical parameters such as magnetic field and temperature.

Effects of different drying methods on the chemical constituents of Lilium lancifolium Thunb. based on UHPLC-MS analysis and antidepressant activity of the main chemical component regaloside A.

The Lilium lancifolium Thunb. is a herb with multiple functions in both medicine and food in China, and its extracts have shown antidepressant effects. In this study, fresh bulbs of Lilium lancifolium Thunb. were processed to study the effects of different drying processes on changes in its main chemical components. We found that different drying methods can affect the chemical constituents of the herb. Among these components, Regaloside A has been found as the characteristic component. Here, Cell Counting Kit-8 assay, and Western blotting were used to evaluate the neuroprotective antidepressant effects of Regaloside A. The results showed the cell survival rate was improved, the phosphorylation levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphatidylinositol 3 kinase, protein kinase B, and mammalian target of rapamycin were increased after Regaloside A treatment. In general, different drying methods have a significant influence on the chemical composition of the herb, and Regaloside A may be the main chemical component of the herb. It can alleviate the damage of corticosterone in SH-SY5Y cells, and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling mediated by brain-derived neurotrophic factor/tyrosine kinase receptor B may play an important role in the neuroprotective antidepressant effects of Regaloside A.

Fading noise reduction in distributed acoustic sensing using an optimal weighted average algorithm.

To the best of our knowledge, we present what we believe is a novel approach for fading noise reduction in distributed acoustic sensing (DAS). Rayleigh signals in multiple optical modes are collected by a phase-sensitive optical time-domain reflectometry system with a diversity detection scheme. An optimal weighted average algorithm is proposed to synthesize the phase demodulated from the Rayleigh signals, leading to the aggregate phase that presents acoustic signals with optimal fading noise reduction. The validity of the proposed approach is experimentally confirmed by comparison of the fading noise along a 12.8 km sensing fiber in a conventional DAS system and a DAS system that employs the proposed approach.

SNR dependence of measurement stability of heterodyne phase-sensitive optical time-domain reflectometry.

Phase-sensitive optical time-domain reflectometry (Φ-OTDR) implements distributed vibration measurements by demodulation of vibration-induced phase of Rayleigh backscattered light waves (RBLs), and suffers from measurement instability. The weak intensities of RBLs and the resulting low signal-to-noise ratios (SNRs) of intensity measurements are the dominating factors that cause the instability of vibration measurements. In this paper, dependence of the measurement stability of heterodyne Φ-OTDR on the SNR of the intensity measurement is investigated analytically and experimentally. An analytical solution of the probability density function of the demodulated phase as a function of SNR is obtained through rigorous derivation, and the dependence of the measurement stability on the SNR is investigated by analyzing the probability density function distribution of the demodulated phase. Both the theoretical predictions and experimental results reveal the impact of SNR on the measurement stability of heterodyne Φ-OTDR. This study fulfills the Φ-OTDR theory and would lead to an effective approach to stabilizing vibration quantization.

Low-noise and high-sensitivity Φ-OTDR based on an optimized dual-pulse heterodyne detection scheme.

In this paper, a novel phase-sensitive optical time-domain reflectometry ($\Phi $Φ-OTDR) based on the optimized dual-pulse heterodyne detection scheme (DHDS) is proposed, which is designed to implement distributed vibration sensing with low phase noise and high sensitivity. The optimized DHDS employs an unbalanced interferometer to separate a light pulse into dual probe pulses so that they are generated by the laser at the same time. This ensures that the measurement sensitivity of a phase-interrogation-based $\Phi $Φ-OTDR can be improved simply by increasing the space interval of the dual probe pulses while the phase noise of the $\Phi $Φ-OTDR does not deteriorate. In addition, the proposed DHDS utilizes only one acousto-optic modulator (AOM) to shift the frequencies of the dual probe pulses so as to eliminate the effects of frequency shift jitters, and thus guarantees low phase noise level of a $\Phi $Φ-OTDR. The distributed vibration sensing performances of the $\Phi $Φ-OTDR with the proposed DHDS are theoretically and experimentally studied in terms of multi-event signal restoration and phase noise level. The proposed approach solves the contradiction between the measurement sensitivity and phase noise of a $\Phi $Φ-OTDR and promotes the $\Phi $Φ-OTDR to the applications of distributed weak vibration sensing.

A Data Fusion Orientation Algorithm Based on the Weighted Histogram Statistics for Vector Hydrophone Vertical Array.

In this paper, we propose a data fusion algorithm based on the weighted histogram statistics (DF-WHS) to improve the performance of direction-of-arrival (DOA) estimation for the vector hydrophone vertical array (VHVA). The processing frequency band is firstly divided into multiple sub-bands, and the high-resolution multiple signal classification (MUSIC) algorithm is applied to estimate the azimuth of each sub-band for each vector hydrophone. Then, the weighted least square (WLS) data fusion technique is used to fuse the sub-band estimation results of multiple sensors. Finally, the weighted histogram statistics method is employed to obtain the synthesis results in the frequency domain. We carried out a simulation and sea trial of the 16-element VHVA to evaluate the performance of the proposed algorithm. Compared to several traditional processing algorithms, the beam width of the proposed approach is significantly narrower, the side lobes are considerably lower, and the mean square error (MSE) is effectively smaller. In addition, the DF-WHS method is more suitable to accurately estimate the target azimuth with a low signal-to-noise ratio (SNR) because the noise sub-band is suppressed in the weighted histogram statistics step. The DF-WHS method in this article provides a new approach to improve the performance of deep-sea target detection for the VHVA.

A Method to Eliminate the Influence of Frequency-Modulating-Induced Auxiliary Amplitude Modulation on the Calibration of 3 × 3 Coupler Asymmetric Parameters.

The 3 × 3 demodulation algorithm has been widely used in retrieving the phase information in the optical fiber sensing system, while the asymmetry of the 3 × 3 coupler can introduce some distortions. In this situation, the parameters of the 3 × 3 coupler can be calibrated by the ellipse fitting method to remove the distortions. Conducting a frequency modulation on the laser, together with an unbalanced Michelson interferometer, makes the ellipse fitting method implemented, which is more appropriate for all-optical sensing. Unexpectedly, the auxiliary amplitude modulation of the laser induced by the frequency modulation is inevitable, leading to the deterioration of the calibration. In this paper, the influence of the auxiliary amplitude modulation on the calibration of the asymmetric parameters is analyzed theoretically and verified experimentally, on the basis of which a convenient but highly efficient method for acquiring the output of the laser and removing related items from the interferometric signals is put forward. The feasibility and robustness of the proposed solution is tested experimentally, and the results show that the mean square errors of the fittings and the variation coefficients of the calibrated parameter sequences are at the scale of 10-5 and 10-4, respectively, indicating that the method performs very well.

Expansion-Prone Hematoma: Defining a Population at High Risk of Hematoma Growth and Poor Outcome.

BACKGROUND: Noncontrast computed tomography (CT) markers are increasingly used for predicting hematoma expansion. The aim of our study was to investigate the predictive value of expansion-prone hematoma in predicting hematoma expansion and outcome in patients with intracerebral hemorrhage (ICH). METHODS: Between July 2011 and January 2017, ICH patients who underwent baseline CT scan within 6 h of symptoms onset and follow-up CT scan were recruited into the study. Expansion-prone hematoma was defined as the presence of one or more of the following imaging markers: blend sign, black hole sign, or island sign. The diagnostic performance of blend sign, black hole sign, island sign, and expansion-prone hematoma in predicting hematoma expansion was assessed. Predictors of hematoma growth and poor outcome were analyzed using multivariable logistical regression analysis. RESULTS: A total of 282 patients were included in our final analysis. Of 88 patients with early hematoma growth, 69 (78.4%) had expansion-prone hematoma. Expansion-prone hematoma had a higher sensitivity and accuracy for predicting hematoma expansion and poor outcome when compared with any single imaging marker. After adjustment for potential confounders, expansion-prone hematoma independently predicted hematoma expansion (OR 28.33; 95% CI 12.95-61.98) and poor outcome (OR 5.67; 95% CI 2.82-11.40) in multivariable logistic model. CONCLUSION: Expansion-prone hematoma seems to be a better predictor than any single noncontrast CT marker for predicting hematoma expansion and poor outcome. Considering the high risk of hematoma expansion in these patients, expansion-prone hematoma may be a potential therapeutic target for anti-expansion treatment in future clinical studies.

Suppression of spontaneous modulation instability and phase noise with a coherent seed in the interferometric fiber sensing systems.

A method is proposed to suppress spontaneous modulation instability (MI) and phase noise with a coherent seed in the interferometric fiber sensing systems. By generating coherent seeds with phase modulation, induced MI is excited in an optical fiber. The preferential gain of the coherent seeds compared to the amplified spontaneous emission noise suppresses spontaneous MI. As a result, the induced MI dominates in the optical fiber. The coherence of the output light is enhanced, and the phase noise is suppressed significantly. The maximum input power can be increased significantly, and the sensing range can be extended.

Reliable Acoustic Path and Direct-Arrival Zone Spatial Gain Analysis for a Vertical Line Array.

A method is developed in this paper to calculate the spatial gain of a vertical line array when the plane-wave assumption is not applicable and when the oceanic ambient noise is correlated. The proposed optimal array gain (OAG), which can evaluate the array's performance and effectively guide its deployment, can be given by an equation in which the noise gain (NG) is subtracted from the signal gain (SG); hence, a high SG and a negative NG can enhance the performance of the array. OAGs and SGs with different array locations are simulated and analyzed based on the sound propagation properties of the direct-arrival zone (DAZ) and the reliable acoustic path (RAP) using ray theory. SG and NG are related to the correlation coefficients of the signals and noise, respectively, and the vertical correlation is determined by the structures of the multipath arrivals. The SG in the DAZ is always high because there is little difference between the multipath waves, while the SG in the RAP changes with the source-receiver range because of the variety of structure in the multiple arrivals. The SG under different conditions is simulated in this work. The "dual peak" structure can often be observed in the vertical directionality pattern of the noise because of the presence of bottom reflection and deep sound channel. When the directions of the signal and noise are close, the conventional beamformer will enhance the correlation of not only the signals but also the noise; thus, the directivity of the signals and noise are analyzed. Under the condition of having a typical sound speed profile, the OAG in some areas of the DAZ and RAP can achieve high values and even exceed the ideal gain of horizontal line array 10 logN dB, while, in some other areas, it will be lowered because of the influence of the NG. The proposed method of gain analysis can provide analysis methods for vertical arrays in the deep ocean under many conditions with references. The theory and simulation are tested by experimental data.

Extrapolation of Elementary Rate Constants of P-glycoprotein-Mediated Transport from MDCKII-hMDR1-NKI to Caco-2 Cells.

The best parameters for incorporation into mechanistic physiologically based pharmacokinetic models for transporters are system-independent kinetic parameters and active (not total) transporter levels. Previously, we determined the elementary rate constants for P-glycoprotein (P-gp)-mediated transport (on- and off-rate constants from membrane to P-gp binding pocket and efflux rate constant into the apical chamber) using the structural mass action kinetic model in confluent MDCKII-hMDR1-NKI cell monolayers. In the present work, we extended the kinetic analysis to Caco-2 cells for the first time and showed that the elementary rate constants are very similar compared with MDCKII-hMDR1-NKI cells, suggesting they primarily depend on the interaction of the compound with P-gp and are therefore mostly independent of the in vitro system used. The level of efflux active (not total) P-gp is also fitted by our model. The estimated level of efflux active P-gp was 5.0 ± 1.4-fold lower in Caco-2 cells than in MDCKII-hMDR1-NKI cells. We also kinetically identified the involvement of a basolateral uptake transporter for both digoxin and loperamide in Caco-2 cells, as found previously in MDCKII-hMDR1-NKI cells, due to their low passive permeability. This demonstrates the value of our P-gp structural model as a diagnostic tool in detecting the importance of other transporters, which cannot be unambiguously done by the Michaelis-Menten approach. The system-independent elementary rate constants for P-gp obtained in vitro are more fundamental parameters than those obtained using Michaelis-Menten steady-state equations. This suggests they will be more robust mechanistic parameters for incorporation into physiologically based pharmacokinetic models for transporters.

53-dB phase noise suppression and Hz-range linewidth emission in compact Brillouin/erbium fiber laser.

We demonstrate 53-dB phase noise reduction in a compact Brillouin/erbium fiber laser (BEFL), which uses 4-m erbium-doped-fiber (EDF) providing both the Brillouin gain and linear gain. A 360-kHz-linewidth laser diode is used as the Brillouin pump (BP) and excites the Brillouin Stokes light. The linewidth of the BEFL is estimated 1.8-Hz based on the correlation between the linewidth and phase noise. Experimental result demonstrates 6-Hz linewidth by beating the emission of two compact BEFLs. This fiber laser provides a simple and effective method to reduce laser phase noise and realize ultra-narrow-linewidth light. It presents many applications in such as interferometric fiber sensing, coherent optical communications, optical clocks, and precise spectroscopy.

Microvilli Morphology Can Affect Efflux Active P-Glycoprotein in Confluent MDCKII -hMDR1-NKI and Caco-2 Cell Monolayers.

From fits of drug transport kinetics across confluent MDCKII-hMDR1-NKI and Caco-2 cell monolayers we estimated the levels of efflux active P-glycoprotein (P-gp) in these two cell lines (companion paper). In the present work, we compared the efflux active P-gp number to the total P-gp level, using liquid chromatography-tandem mass spectrometry, and showed that in Caco-2 cells total P-gp is about 10-fold greater than efflux active P-gp, whereas in MDCKII-hMDR1-NKI cells these values are within twofold. We further visualized the microvilli in MDCKII-hMDR1-NKI and Caco-2 cells using three-dimensional structured illumination super-resolution microscopy and found that the microvilli in Caco-2 cells are taller and more densely packed than those in MDCK-hMDR1-NKI cells. We hypothesized over 10 years ago that only P-gp at the tips of the microvilli contribute significantly to efflux activity, whereas the remaining P-gp are involved in a futile cycle of efflux of amphipathic drugs from the microvillus membrane, followed by their reabsorption into the same or nearby microvillous membranes. The difference between the levels of total and efflux active P-gp in Caco-2 cells can be explained by the more densely packed microvilli in Caco-2 cells, which would lead to a substantial fraction of P-gp not contributing to final release of drug into the apical chamber. Our results suggest that the effect of microvilli morphology differences between in vitro and in vivo systems must be considered when scaling transporter activity for efflux transporters of amphipathic compounds, for example, P-gp.