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.

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.

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.

Photon-Phonon Atomic Coherence Interaction of Nonlinear Signals in Various Phase Transitions Eu3+: BiPO4.

We report photon-phonon atomic coherence (cascade- and nested-dressing) interaction from the various phase transitions of Eu3+: BiPO4 crystal. Such atomic coherence spectral interaction evolves from out-of-phase fluorescence to in-phase spontaneous four-wave mixing (SFWM) by changing the time gate. The dressing dip switch and three dressing dips of SFWM result from the strong photon-phonon destructive cross- and self-interaction for the hexagonal phase, respectively. More phonon dressing results in the destructive interaction, while less phonon dressing results in the constructive interaction of the atomic coherences. The experimental measurements of the photon-phonon interaction agree with the theoretical simulations. Based on our results, we proposed a model for an optical transistor (as an amplifier and switch).

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.

Prediction of tumor recurrence by distinct immunoprofiles in liver transplant patients based on mass cytometry.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is a marker of poor prognosis. However, the reliable biomarkers of post-LT HCC recurrence remain to be identified. In this study, serial peripheral blood samples from the LT recipients with and without HCC recurrence were collected at five time points. Single-cell mass cytomertry (CyTOF) was utilized for the in-depth analysis of peripheral blood monocellular cells (PBMCs). CyTOF analysis showed that at 3 weeks post-LT, the activated immune cell population was increased, while the fraction of immune cells with suppressive functions (myeloid-derived suppressive cells) was reduced. The post-LT immune composition in patients with LT for HCC was enormously different from that in patients with LT for causes other than HCC. Furthermore, at 3 weeks after LT, compared with patients without recurrence, the patients with HCC recurrences were high in two subsets of T cells: CD57+ HLA-DR+ CD8+ and CD28+γδ. The CD57+ HLA-DR+ CD8+ T cells presented high levels of perforin, granzyme B, and Ki-67 and displayed a highly cytotoxic and proliferative phenotype, while the CD28+γδ T cells had reduced levels of IFN-γ and, hence, were less activated compared to CD28- cells. Based on these findings, we concluded that analyzing the PBMCs of LT recipients by CyTOF can predict the post-LT HCC recurrence. The distinct immune features can stratify patients with the risk of HCC recurrence at 3 weeks after LT, which will help clinician in further management plan and improve the prognosis of patients.

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.

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.

High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma.

Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.

Prediction model based on blood urea nitrogen and the leukocyte count for intestinal necrosis in patients with portal vein system thrombosis: a retrospective study.

BACKGROUND: Portal vein system thrombosis (PVST) is a serious and potentially fatal disease. No definite parameter can predict intestinal necrosis in patients with PVST to justify early surgical intervention. The current study aimed to explore a simple and accurate model to predict the occurrence of intestinal necrosis in patients with PVST. METHODS: Records of patients admitted to our emergency department with PVST from January 2010 to October 2018 were reviewed. Clinical parameters, including patient history, physical examination, and the results of laboratory investigations, were analyzed. RESULTS: Sixty-nine patients (27 females) were included. All patients were admitted to our emergency department because of abdominal pain. Fourteen patients required exploratory laparotomy, and intestinal necrosis was confirmed. Seven patients received thrombolytic therapy, and the other 48 patients had completed anticoagulation successfully. According to multivariate logistic regression, high blood urea nitrogen (BUN) (OR: 1.413, P=0.048) and the leukocyte count (OR: 1.180, P=0.005) were associated with intestinal necrosis, and a prediction model for intestinal necrosis (PMIN) based on the BUN and leukocyte count was established. CONCLUSIONS: The PMIN score could effectively predict intestinal necrosis in patients with PVST.

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.

Multi-mode of Four and Six Wave Parametric Amplified Process.

Multiple quantum modes in correlated fields are essential for future quantum information processing and quantum computing. Here we report the generation of multi-mode phenomenon through parametric amplified four- and six-wave mixing processes in a rubidium atomic ensemble. The multi-mode properties in both frequency and spatial domains are studied. On one hand, the multi-mode behavior is dominantly controlled by the intensity of external dressing effect, or nonlinear phase shift through internal dressing effect, in frequency domain; on the other hand, the multi-mode behavior is visually demonstrated from the images of the biphoton fields directly, in spatial domain. Besides, the correlation of the two output fields is also demonstrated in both domains. Our approach supports efficient applications for scalable quantum correlated imaging.

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.

Switching Correlation and Noise Level in Pr(3+):YSO Crystal via Dressing Nonlinear Phase.

We propose and experimentally demonstrate that the intensity noise correlation and the noise level of intensity-difference and intensity-sum in Stokes and anti-Stokes channel can be well controlled by the relative nonlinear phase in spontaneous parametric four-wave mixing process. By modulating the relative nonlinear phase, including self-phase modulation and cross-phase modulation, switching the correlation into anti-correlation and the relative intensity noise level between the intensity-difference and intensity-sum are realized. We also show that the variation tendencies of the relative intensity noise level and the corresponding intensity fluctuations correlation are in accordance with each other.

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.

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.