Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation.

BACKGROUND AND AIMS: Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue. METHODS: Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles. RESULTS: HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT. CONCLUSIONS: FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.

Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

Angular-Dependent Klein Tunneling in Photonic Graphene.

The Klein paradox consists in the perfect tunneling of relativistic particles through high potential barriers. It is responsible for the exceptional conductive properties of graphene. It was recently studied in atomic condensates and topological photonics and phononics. While in theory the perfect tunneling holds only for normal incidence, so far the angular dependence of the Klein tunneling and its strong variation with the barrier height were not measured experimentally. In this Letter, we capitalize on the versatility of atomic vapor cells with paraxial beam propagation and index patterning by electromagnetically induced transparency. We report the first experimental observation of perfect Klein transmission in a 2D photonic system (photonic graphene) at normal incidence and measure the angular dependence. Counterintuitively, but in agreement with the Dirac equation, we observe that the decay of the Klein transmission versus angle is suppressed by increasing the barrier height, a key result for the conductivity of graphene and its analogs.

Regulatory T Cell Therapy Following Liver Transplantation.

Liver transplantation (LT) is considered the gold standard of curative treatment for patients with end-stage liver disease or nonresectable hepatic malignant tumors. Rejection after LT is the main nontechnical factor affecting the prognosis of recipients. Medical and surgical advances, combined with improved immunosuppression with drugs such as calcineurin inhibitors (CNIs), have contributed to an increase in 1-year graft survival to around 80%. However, medium- and long-term improvements in LT outcomes have lagged behind. Importantly, CNIs and other classical immunosuppressive drugs are associated with significant adverse effects, including malignancies, cardiovascular disease, and severe renal dysfunction. Immunomodulation using regulatory T cells (Tregs) is emerging as a promising alternative to classical immunosuppression. Since their discovery, the immunomodulatory effects of Tregs have been demonstrated in a range of diseases. This has rejuvenated the interest in using Tregs as a therapeutic strategy to induce immune tolerance after LT. In this review, we first summarize the discovery and development of Tregs. We then review the preclinical data supporting their production, mechanism of action, and therapeutic efficacy followed by a summary of relevant clinical trials. Finally, we discuss the outstanding challenges of Treg therapy and its future prospects for routine use in LT.

Talbot effect of an electromagnetically induced square photonic lattice assisted by a spatial light modulator.

We demonstrate the Talbot effect of an electromagnetically induced square photonic lattice formed under the electromagnetically induced transparency (EIT) condition both experimentally and theoretically in a three-level 85Rb atomic configuration. The two-dimensional lattice patterns result from the diffraction of a Gaussian probe field traveling through the vapor cell, in which the refractive index is modulated by a coupling field with a two-dimensional periodic intensity distribution generated by a spatial light modulator. The experimental observations are consistent with the theoretical predictions. This investigation not only provides a new avenue for producing desired electromagnetically induced photonic lattices beyond the commonly adopted multi-beam interfering method but also broadens studies of electromagnetically induced Talbot effect to two-dimensional space.

Transport of light in a moving photonic lattice via atomic coherence.

In this Letter, we have investigated experimentally the photonic realization of a moving lattice with an instantaneously tunable transverse velocity in a three-level Λ-type warm 85Rb atomic medium. The dynamic photonic lattice moving along the direction of its spatial periodicity was constructed by introducing a frequency difference (determining the velocity) between two coupling beams, whose interference pattern could optically induce a (spatial) periodic refractive index change inside the atomic vapor under electromagnetically induced transparency. When a Gaussian probe field is launched into this optically induced lattice, the output diffraction patterns can shift along the transverse direction, indicating dynamical features of induced photonic structures. The realization of this effectively controllable moving photonic lattice provides a new platform for guiding the transport of light.

Biological functions and clinical applications of exosomal non-coding RNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.

Particlelike Behavior of Topological Defects in Linear Wave Packets in Photonic Graphene.

Topological defects, such as quantum vortices, determine the properties of quantum fluids. Their study has been at the center of activity in solid state and BEC communities. In parallel, the nontrivial behavior of linear wave packets with complex phase patterns was investigated by singular optics. Here, we study the formation, evolution, and interaction of optical vortices in wave packets at the Dirac point in photonic graphene. We show that while their exact behavior goes beyond the Dirac equation and requires a full account of the lattice properties, it can be still approximately described by an effective theory considering the phase singularities as "particles". These particles are capable of mutual interaction, with their trajectory obeying the laws of dynamics.

Correlation and squeezing for optical transistor and intensity for router applications in Pr3+:YSO.

We realized an optical transistor and router utilizing multi-order fluorescence and spontaneous parametric four-wave mixing. Specifically, the optical routing action was derived from the results of splitting in the intensity signal due to a dressing effect, whereas the transistor as a switch and amplifier was realized by a switching correlation and squeezing via a nonlinear phase. A substantial enhancement of the optical contrast was observed for switching applications using correlation and squeezing contrary to the intensity signal. Moreover, the controlling parameters were also configured to devise a control mechanism for the optical transistor and router.

Controllable circular Airy beams via dynamic linear potential.

We investigate controllable spatial modulation of circular autofocusing Airy beams, under action of different dynamic linear potentials, both theoretically and numerically. We introduce a novel treatment method in which the circular Airy beam is represented as a superposition of narrow azimuthally-modulated one-dimensional Airy beams that can be analytically treated. The dynamic linear potentials are appropriately designed, so that the autofocusing effect can either be weakened or even eliminated when the linear potential exerts a "pulling" effect on the beam, or if the linear potential exerts a "pushing" effect, the autofocusing effect can be greatly strengthened. Numerical simulations agree with the theoretical results very well.

Nonparaxial self-accelerating beams in an atomic vapor with electromagnetically induced transparency.

We theoretically and numerically investigate the nonparaxial self-accelerating beams in a Λ-type three-level energy system of rubidium atomic vapor in the electromagnetically induced transparency (EIT) window. In the EIT window, the absorption of the atomic vapor is small, and robust nonparaxial self-accelerating beams can be generated. The reason is that the energy of the tail transfers to the main lobe, which then maintains its shape, owing to the self-healing effect. Media with large absorption would demand large energy to compensate, and the tail would be lifted too high to maintain the profile of an accelerating beam, so that self-accelerating beams cannot be obtained any longer. An atomic vapor with small absorption is the ideal medium to produce such self-accelerating beams and, in return, self-accelerating beams may inspire new ideas in the research associated with atomic vapors and atomic-like ensembles.

Fractional nonparaxial accelerating Talbot effect.

We demonstrate the fractional Talbot effect of nonparaxial accelerating beams, theoretically and numerically. It is based on the interference of nonparaxial accelerating solutions of the Helmholtz equation in two dimensions. The effect originates from the interfering lobes of a superposition of the solutions that accelerate along concentric semicircular trajectories with different radii. Talbot images form along certain central angles, which are referred to as Talbot angles. The fractional nonparaxial Talbot effect is obtained by choosing the coefficients of beam components properly. A single nonparaxial accelerating beam possesses duality-it can be viewed as a Talbot effect of itself with an infinite or zero Talbot angle. These results improve the understanding of the nonparaxial accelerating beams and of the Talbot effect among them.

Dressed intensity noise correlation and intensity-difference squeezing of spontaneous parametric four-wave mixing process in a Pr³âº:YSO crystal.

We report dressed intensity noise correlation and intensity-difference squeezing based on spontaneous parametric four-wave mixing (SP-FWM) in Pr³âº:Y2SiO5 crystal both experimentally and theoretically. We found such intensity noise correlation and intensity-difference squeezing can be controlled by using the dressing effect to manipulate the nonlinear optical coefficient of the SP-FWM process. By changing detuning and power of the optical field, we manipulate the nonlinear optical coefficient of the SP-FWM process, thus control the correlation and squeezing. The results show stronger correlation and squeezing with single dressing, while weaker near the resonant point due to destructive double dressing. Furthermore,we observed the dependence of correlation times on the power of dressing field, and explained by the combination of the dressing effect and induced dipole-dipole interaction. We also showed the fourth-order fluorescence signals accompanying with the SP-FWM process.

Ultrafast optical transistor and router of multi-order fluorescence and spontaneous parametric four-wave mixing in Pr³âº:YSO.

We study the realization of an optical transistor (switch and amplifier) and router in multi-order fluorescence (FL) and spontaneous parametric four-wave mixing (SP-FWM). We estimate that the switching speed is about 15 ns. The router action results from the Autler-Townes splitting in spectral or time domain. The switch and amplifier are realized by dressing suppression and enhancement in FL and SP-FWM. The optical transistor and router can be controlled by multi-parameters (i.e., power, detuning, or polarization).

Modulating the correlation and squeezing of phase-conjugate four-wave mixing via the polarizable dressing states.

We report the experimental observation of the intensity noise correlation and squeezing between counter propagating Stokes and anti-Stokes signals in Pr(3+):Y2SiO5 crystals. Both the degree of correlation and squeezing as well as the oscillation frequency of correlation curves are modulated by changing the polarization states and powers of the dressing fields. The double-dressed effect and the triple-dressed effect in V-type three-level, Λ-type three-level and N-type four-level systems are compared. The polarization and power dependencies in these systems are different, and the oscillation frequency of the correlation curve in the triple-dressed process is greater than that of the double-dressed process. Our results show that the correlation and squeezing of photon pairs can be controlled via polarized dark states.

Interactions of Airy beams, nonlinear accelerating beams, and induced solitons in Kerr and saturable nonlinear media.

We investigate numerically interactions between two in-phase or out-of-phase Airy beams and nonlinear accelerating beams in Kerr and saturable nonlinear media in one transverse dimension. We discuss different cases in which the beams with different intensities are launched into the medium, but accelerate in opposite directions. Since both the Airy beams and nonlinear accelerating beams possess infinite oscillating tails, we discuss interactions between truncated beams, with finite energies. During interactions we see solitons and soliton pairs generated that are not accelerating. In general, the higher the intensities of interacting beams, the easier to form solitons; when the intensities are small enough, no solitons are generated. Upon adjusting the interval between the launched beams, their interaction exhibits different properties. If the interval is large relative to the width of the first lobes, the generated soliton pairs just propagate individually and do not interact much. However, if the interval is comparable to the widths of the maximum lobes, the pairs strongly interact and display varied behavior.

Polarization dressed multi-order fluorescence of Pr³âº:Y2SiO5.

We report polarization dressed second-, fourth- and sixth-order fluorescence processes in a Pr(3+):Y2SiO5 crystal. By changing the polarization states of dressing fields and generating fields, the fluorescence baselines, suppression and Autler-Townes splitting of emission peaks can be controlled. The polarization dependencies of fluorescence generated from two inequivalent crystallographic sites are compared. The experimental results agree with the dressing theoretical calculations well.

Suppression and enhancement of coexisting super-fluorescence and multi-wave mixing processes in sodium vapor.

Different aspects of the properties of the coexisting super-fluorescence (SFL), multi-wave mixing with the fluorescence signal in the sodium vapor are studied both theoretically and experimentally. First, by scanning the dressed-state, the properties of these coexisting processes, such as the SFL signal modulated by using the dark and bright states, the interplay between dressed-states, are observed for the first time. Then, by scanning the probe field, the interplay between the one-photon and two-photon processes of the coexisting signals is obtained with or without the external dressing fields. Such control on each process in such coexisting system has an important potential application in quantum communication.

Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis.

Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of ferroptosis or ACSL4 abrogated the effects of gp78 on ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.