LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.

Magnetic resonance diffusion tensor imaging of cervical microstructure in normal early and late pregnancy in vivo.

BACKGROUND: Cervical remodeling is an important aspect of birth timing. Before cervical ripening, the collagen fibers are arranged in a closely interweaved network, but during ripening, the fibers become disorganized and the cervix becomes more hydrated. To quantitatively measure cervical remodeling, we need a noninvasive method to monitor changes in cervical collagen fiber organization and hydration in vivo. OBJECTIVE: To use diffusion tensor imaging to image and quantify the spatial and temporal differences in cervical microstructure between normal early and late pregnancies. STUDY DESIGN: After institutional review board approval and consent, a group of healthy women in early pregnancy (22 patients at 12-14 weeks' gestation) and a group in late pregnancy (27 patients at 36-38 weeks' gestation) underwent magnetic resonance imaging on a Siemens MAGNETOM Vida 3 Tesla unit. Diffusion tensor imaging of the cervix in the axial plane was performed with a two-dimensional single-shot echo planar imaging diffusion-weighted sequence. In early and late pregnancy groups, the differences of the diffusion tensor imaging measures were compared between the subglandular zone and the outer stroma regions of the cervix. In addition, the diffusion tensor imaging measures were compared between the early and late pregnancy groups. Finally, for the late pregnancy group, the diffusion tensor imaging measures were compared between the primipara and multipara groups. RESULTS: Diffusion tensor imaging measures of microstructure significantly differed between the subglandular zone and outer stroma regions of the cervix in both early and late pregnancies. In the subglandular zone, fractional anisotropy was lower in the late pregnancy group than in the early pregnancy group (0.37 [0.34-0.42] vs 0.50 [0.43-0.58]; P<.0005), suggesting increased collagen fiber disorganization in this zone. In addition, mean diffusivity was higher in the late pregnancy group than in the early pregnancy group (1.84 [1.73-2.02] mm2/sec×10-3 vs 1.56 [1.42-1.69] mm2/sec×10-3; P=.001), suggesting increased hydration in the subglandular zone. In the outer stroma, neither fractional anisotropy (0.44 [0.40-0.50] vs 0.41 [0.37-0.43]; P=.095) nor mean diffusivity (2.09 [1.92-2.25] mm2/sec×10-3 vs 2.12 [2.04-2.24] mm2/sec×10-3; P=.269) significantly differed between early pregnancy and late pregnancy, suggesting insignificant temporal microstructural changes in this cervical zone. Diffusion tensor imaging measures did not significantly differ between cervixes from primiparous and multiparous women in late pregnancy. CONCLUSION: This in vivo study demonstrates that diffusion tensor imaging can noninvasively quantify the microstructural differences in collagen fiber organization and hydration in cervical subregions between early pregnancy and late pregnancy.

Regulation of TP73 transcription by Hippo-YAP signaling.

Yes-associated protein (YAP) is a key downstream effector of the highly conserved Hippo signaling pathway, which regulates organ size, regeneration and tumorigenesis. Known classically to function as a transcriptional co-activator, YAP interacts with TEA domain transcription factors (TEAD1-4) to induce expression of target genes. However, a number of genes are repressed upon YAP activation, suggesting a transcriptional repressor role of YAP. Here, we report that TP73 is a direct target gene of YAP, and its transcription is repressed by YAP in a TEAD-independent manner. On the other hand, WW domains of YAP are indispensable for the regulation of TP73 expression, which may recruit YAP to TP73 gene though interaction with ZEB1 and/or RUNX2, two transcriptional repressors. Moreover, YAP-mediated repression of TP73 promotes cancer cell survival in the presence of chemotherapeutic agents, suggesting YAP-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies.

Effect of PT symmetry on nonlinear waves for three-wave interaction models in the quadratic nonlinear media.

We study the three-wave interaction that couples an electromagnetic pump wave to two frequency down-converted daughter waves in a quadratic optical crystal and PT-symmetric potentials. PT symmetric potentials are shown to modulate stably nonlinear modes in two kinds of three-wave interaction models. The first one is a spatially extended three-wave interaction system with odd gain-and-loss distribution in the channel. Modulated by the PT-symmetric single-well or multi-well Scarf-II potentials, the system is numerically shown to possess stable soliton solutions. Via adiabatical change of system parameters, numerical simulations for the excitation and evolution of nonlinear modes are also performed. The second one is a combination of PT-symmetric models which are coupled via three-wave interactions. Families of nonlinear modes are found with some particular choices of parameters. Stable and unstable nonlinear modes are shown in distinct families by means of numerical simulations. These results will be useful to further investigate nonlinear modes in three-wave interaction models.

Three-component Gross-Pitaevskii equations in the spin-1 Bose-Einstein condensate: Spin-rotation symmetry, matter-wave solutions, and dynamics.

We report new matter-wave solutions of the one-dimensional spin-1 Bose-Einstein condensate system by combining global spin-rotation states and similarity transformation. Dynamical behaviors of non-stationary global spin-rotation states derived from the SU(2) spin-rotation symmetry are discussed, which exhibit temporal periodicity. We derive generalized bright-dark mixed solitons and new rogue wave solutions and reveal the relations between Euler angles in spin-rotation symmetry and parameters in ferromagnetic and polar solitons. In the modulated spin-1 Bose-Einstein condensate system, new solutions are derived and graphically illustrated for different types of modulations. Moreover, numerical simulations are performed to investigate the stability of some obtained solutions for chosen parameters.

Solitons and their stability in the nonlocal nonlinear Schrödinger equation with PT-symmetric potentials.

We report localized nonlinear modes of the self-focusing and defocusing nonlocal nonlinear Schrödinger equation with the generalized PT-symmetric Scarf-II, Rosen-Morse, and periodic potentials. Parameter regions are presented for broken and unbroken PT-symmetric phases of linear bounded states and the linear stability of the obtained solitons. Moreover, we numerically explore the dynamical behaviors of solitons and find stable solitons for some given parameters.

On stable solitons and interactions of the generalized Gross-Pitaevskii equation with PT- and non- PT-symmetric potentials.

We report the bright solitons of the generalized Gross-Pitaevskii (GP) equation with some types of physically relevant parity-time- ( PT-) and non- PT-symmetric potentials. We find that the constant momentum coefficient Γ can modulate the linear stability and complicated transverse power-flows (not always from the gain toward loss) of nonlinear modes. However, the varying momentum coefficient Γ(x) can modulate both unbroken linear PT-symmetric phases and stability of nonlinear modes. Particularly, the nonlinearity can excite the unstable linear mode (i.e., broken linear PT-symmetric phase) to stable nonlinear modes. Moreover, we also find stable bright solitons in the presence of non- PT-symmetric harmonic-Gaussian potential. The interactions of two bright solitons are also illustrated in PT-symmetric potentials. Finally, we consider nonlinear modes and transverse power-flows in the three-dimensional (3D) GP equation with the generalized PT-symmetric Scarff-II potential.

3D E-textile for Exercise Physiology and Clinical Maternal Health Monitoring.

Electronic textiles (E-textiles) offer great wearing comfort and unobtrusiveness, thus holding potential for next-generation health monitoring wearables. However, the practical implementation is hampered by challenges associated with poor signal quality, substantial motion artifacts, durability for long-term usage, and non-ideal user experience. Here, we report a cost-effective E-textile system that features 3D microfiber-based electrodes for greatly increasing the surface area. The soft and fluffy conductive microfibers disperse freely and securely adhere to the skin, achieving a low impedance at the electrode-skin interface even in the absence of gel. A superhydrophobic fluorinated self-assembled monolayer was deposited on the E-textile surface to render it waterproof while retaining the electrical conductivity. Equipped with a custom-designed motion-artifact canceling wireless data recording circuit, the E-textile system could be integrated into a variety of smart garments for exercise physiology and health monitoring applications. Real-time multimodal electrophysiological signal monitoring, including electrocardiogram (ECG) and electromyography (EMG), was successfully carried out during strenuous cycling and even underwater swimming activities. Furthermore, a multi-channel E-textile was developed and implemented in clinical patient studies for simultaneous real-time monitoring of maternal ECG and uterine EMG signals, incorporating spatial-temporal potential mapping capabilities.

MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation.

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1-/- mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1-/- mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1-/- mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

Noninvasive electrophysiological imaging identifies 4D uterine peristalsis patterns in subjects with normal menstrual cycles and patients with endometriosis.

Throughout the menstrual cycle, spontaneous mild contractions in the inner layer of the uterine smooth muscle cause uterine peristalsis, which plays a critical role in normal menstruation and fertility. Disruptions in peristalsis patterns may occur in women experiencing subfertility, abnormal uterine bleeding, ovulatory dysfunction, endometriosis, and other disorders. However, current tools to measure uterine peristalsis in humans have limitations that hamper their research or clinical utilities. Here, we describe an electrophysiological imaging system to noninvasively quantify the four-dimensional (4D) electrical activation pattern during human uterine peristalsis with high spatial and temporal resolution and coverage. We longitudinally imaged 4968 uterine peristalses in 17 participants with normal gynecologic anatomy and physiology over 34 hours and 679 peristalses in 5 participants with endometriosis over 12.5 hours throughout the menstrual cycle. Our data provide quantitative evidence that uterine peristalsis changes in frequency, direction, duration, magnitude, and power throughout the menstrual cycle and is disrupted in endometriosis patients. Moreover, our data suggest that disrupted uterine peristalsis contributes to excess retrograde menstruation and infertility in patients with endometriosis and potentially contributes to infertility in this cohort.

Electromyometrial Imaging of Uterine Contractions in Pregnant Women.

During normal pregnancy, the uterine smooth muscle, the myometrium, begins to have weak, uncoordinated contractions at late gestation to help the cervix remodel. In labor, the myometrium has strong, coordinated contractions to deliver the fetus. Various methods have been developed to monitor uterine contraction patterns to predict labor onset. However, the current techniques have limited spatial coverage and specificity. We developed electromyometrial imaging (EMMI) to noninvasively map uterine electrical activity onto the three-dimensional uterine surface during contractions. The first step in EMMI is to use T1-weighted magnetic resonance imaging to acquire the subject-specific body-uterus geometry. Next, up to 192 pin-type electrodes placed on the body surface are used to collect electrical recordings from the myometrium. Finally, the EMMI data processing pipeline is performed to combine the body-uterus geometry with body surface electrical data to reconstruct and image uterine electrical activities on the uterine surface. EMMI can safely and noninvasively image, identify, and measure early activation regions and propagation patterns across the entire uterus in three dimensions.

A Portable and a Scalable Multi-Channel Wireless Recording System for Wearable Electromyometrial Imaging.

Electromyometrial imaging (EMMI) technology has emerged as one of the promising technology that can be used for non-invasive pregnancy risk stratification and for preventing complications due to pre-term birth. Current EMMI systems are bulky and require a tethered connection to desktop instrumentation, as a result, the system cannot be used in non-clinical and ambulatory settings. In this article, we propose an approach for designing a scalable, portable wireless EMMI recording system that can be used for in-home and remote monitoring. The wearable system uses a non-equilibrium differential electrode multiplexing approach to enhance signal acquisition bandwidth and to reduce the artifacts due to electrode drifts, amplifier 1/f noise, and bio-potential amplifier saturation. A combination of active shielding, a passive filter network, and a high-end instrumentation amplifier ensures sufficient input dynamic range ([Formula: see text]) such that the system can simultaneously acquire different bio-potential signals like maternal electrocardiogram (ECG) in addition to the EMMI electromyogram (EMG) signals. We show that the switching artifacts and the channel cross-talk introduced due to non-equilibrium sampling can be reduced using a compensation technique. This enables the system to be potentially scaled to a large number of channels without significantly increasing the system power dissipation. We demonstrate the feasibility of the proposed approach in a clinical setting using an 8-channel battery-powered prototype which dissipates less than 8 µW per channel for a signal bandwidth of 1 KHz.

Noninvasive electromyometrial imaging of human uterine maturation during term labor.

Electromyometrial imaging (EMMI) was recently developed to image the three-dimensional (3D) uterine electrical activation during contractions noninvasively and accurately in sheep. Herein we describe the development and application of a human EMMI system to image and evaluate 3D uterine electrical activation patterns at high spatial and temporal resolution during human term labor. We demonstrate the successful integration of the human EMMI system during subjects' clinical visits to generate noninvasively the uterine surface electrical potential maps, electrograms, and activation sequence through an inverse solution using up to 192 electrodes distributed around the abdomen surface. Quantitative indices, including the uterine activation curve, are developed and defined to characterize uterine surface contraction patterns. We thus show that the human EMMI system can provide detailed 3D images and quantification of uterine contractions as well as novel insights into the role of human uterine maturation during labor progression.

Magnetic resonance imaging of the supra-cervical fetal membrane detects an increased risk of prelabor rupture of membranes.

Objective: In 10% of term deliveries and 40% of preterm deliveries, the fetal membrane (FM) ruptures before labor. However, the ability to predict these cases of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) is very limited. In this paper, our objective was to determine whether a prediction method based on T2 weighted magnetic resonance imaging (MRI) of the supra-cervical FM could predict PROM and PPROM. Methods: This prospective cohort study enrolled 77 women between the 28th and 37th weeks of gestation. Two indicators of fetal membrane defects, including prolapsed depth >5 mm and signal abnormalities, are investigated for our prediction. Fisher's exact test was used to determine whether prolapsed depth >5 mm and/or signal abnormalities were associated with PROM and PPROM. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for prolapsed depth >5 mm, signal abnormalities, and the combination of prolapsed depth >5 mm and signal abnormalities. Result: Among 12 women with PROM (5 preterm and 7 term, prior to labor onset), 9 had membrane prolapse >5 mm and 5 had FM signal abnormalities. Among 65 women with rupture of membranes at term, 2 had membrane prolapse >5 mm and 1 had signal abnormalities. By Fisher's exact test both indicators, membrane prolapse >5 mm and signal abnormalities, were associated with PROM (P<0.001, P<0.001) and PPROM (P=0.001, P<0.001). Additionally, membrane prolapse >5 mm, signal abnormalities, and the combination of the two indicators all demonstrated high specificity for predicting PROM (96.9%, 98.5%, and 100%, respectively) and PPROM (90.3%, 97.2%, and 100%, respectively). Conclusion: MRI can distinguish the supra-cervical fetal membrane in vivo and may be able to identify women at high risk of PPROM.

Stretchable Sponge Electrodes for Long-Term and Motion-Artifact-Tolerant Recording of High-Quality Electrophysiologic Signals.

Soft electronic devices and sensors have shown great potential for wearable and ambulatory electrophysiologic signal monitoring applications due to their light weight, ability to conform to human skin, and improved wearing comfort, and they may replace the conventional rigid electrodes and bulky recording devices widely used nowadays in clinical settings. Herein, we report an elastomeric sponge electrode that offers greatly reduced electrode-skin contact impedance, an improved signal-to-noise ratio (SNR), and is ideally suited for long-term and motion-artifact-tolerant recording of high-quality biopotential signals. The sponge electrode utilizes a porous polydimethylsiloxane sponge made from a sacrificial template of sugar cubes, and it is subsequently coated with a poly(3,4-ethylenedioxythiophene) polystyrenesulfonate (PEDOT:PSS) conductive polymer using a simple dip-coating process. The sponge electrode contains numerous micropores that greatly increase the skin-electrode contact area and help lower the contact impedance by a factor of 5.25 or 6.7 compared to planar PEDOT:PSS electrodes or gold-standard Ag/AgCl electrodes, respectively. The lowering of contact impedance resulted in high-quality electrocardiogram (ECG) and electromyogram (EMG) recordings with improved SNR. Furthermore, the porous structure also allows the sponge electrode to hold significantly more conductive gel compared to conventional planar electrodes, thereby allowing them to be used for long recording sessions with minimal signal degradation. The conductive gel absorbed into the micropores also serves as a buffer layer to help mitigate motion artifacts, which is crucial for recording on ambulatory patients. Lastly, to demonstrate its feasibility and potential for clinical usage, we have shown that the sponge electrode can be used to monitor uterine contraction activities from a patient in labor. With its low-cost fabrication, softness, and ability to record high SNR biopotential signals, the sponge electrode is a promising platform for long-term wearable health monitoring applications.

In vivo Assessment of Supra-Cervical Fetal Membrane by MRI 3D CISS: A Preliminary Study.

In approximately 8% of term births and 33% of pre-term births, the fetal membrane (FM) ruptures before delivery. In vitro studies of FMs after delivery have suggested the series of events leading to rupture, but no in vivo studies have confirmed this model. In this study, we used a three-dimensional constructive interference in steady state (3D-CISS) sequence to examine the FM at the cervical internal os zone during pregnancy; 18 pregnant women with one to three longitudinal MRI scans were included in this study. In 14 women, the FM appeared normal and completely intact. In four women, we noted several FM abnormalities including cervical funneling, chorioamniotic separation, and chorion rupture. Our data support the in vitro model that the FM ruptures according to a sequence starting with the stretch of chorion and amnion, then the separation of amnion from chorion, next the rupture of chorion, and finally the rupture of amnion ruptures. These findings hold great promise to help to develop an in vivo magnetic resonance imaging marker that improves examination of the FMs.

Spatial solitons and stability in self-focusing and defocusing Kerr nonlinear media with generalized parity-time-symmetric Scarff-II potentials.

We present a unified theoretical study of the bright solitons governed by self-focusing and defocusing nonlinear Schrödinger (NLS) equations with generalized parity-time- (PT) symmetric Scarff-II potentials. Particularly, a PT-symmetric k-wave-number Scarff-II potential and a multiwell Scarff-II potential are considered, respectively. For the k-wave-number Scarff-II potential, the parameter space can be divided into different regions, corresponding to unbroken and broken PT symmetry and the bright solitons for self-focusing and defocusing Kerr nonlinearities. For the multiwell Scarff-II potential the bright solitons can be obtained by using a periodically space-modulated Kerr nonlinearity. The linear stability of bright solitons with PT-symmetric k-wave-number and multiwell Scarff-II potentials is analyzed in detail using numerical simulations. Stable and unstable bright solitons are found in both regions of unbroken and broken PT symmetry due to the existence of the nonlinearity. Furthermore, the bright solitons in three-dimensional self-focusing and defocusing NLS equations with a generalized PT-symmetric Scarff-II potential are explored. This may have potential applications in the field of optical information transmission and processing based on optical solitons in nonlinear dissipative but PT-symmetric systems.

Hydrogen sulfide is involved in maintaining ion homeostasis via regulating plasma membrane Na+/H+ antiporter system in the hydrogen peroxide-dependent manner in salt-stress Arabidopsis thaliana root.

Hydrogen sulfide (H2S) and hydrogen peroxide (H2O2) function as the signaling molecules in plants responding to salt stresses. The present study presents a signaling network involving H2S and H2O2 in salt resistance pathway of the Arabidopsis root. Arabidopsis roots were sensitive to 100 mM NaCl treatment, which displayed a great increase in electrolyte leakage (EL) and Na(+)/K(+) ratio under salt stress. The treatment of H2S donors sodium hydrosulfide (NaHS) enhanced the salt tolerance by maintaining a lower Na(+)/K(+) ratio. In addition, the inhibition of root growth under salt stress was removed by H2S. Further studies indicated that H2O2 was involved in H2S-induced salt tolerance pathway. H2S induced the production of the endogenous H2O2 via regulating the activities of glucose-6-phosphate dehydrogenase (G6PDH) and plasma membrane (PM) NADPH oxidase, with the treatment with dimethylthiourea (DMTU, an ROS scavenger), diphenylene iodonium (DPI, a PM NADPH oxidase inhibitor), or glycerol (G6PDH inhibitor) removing the effect of H2S. Treatment with amiloride (an inhibitor of PM Na(+)/H(+) antiporter) and vanadate (an inhibitor of PM H(+)-ATPase) also inhibited the activity of H2S on Na(+)/K(+) ratio. Through an analysis of quantitative real-time polymerase chain reaction and Western blot, we found that H2S promoted the genes expression and the phosphorylation level of PM H(+)-ATPase and Na(+)/H(+) antiporter protein level. However, when the endogenous H2O2 level was inhibited by DPI or DMTU, the effect of H2S on the PM Na(+)/H(+) antiporter system was removed. Taken together, H2S maintains ion homeostasis in the H2O2-dependent manner in salt-stress Arabidopsis root.