Interferon-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

Saturable absorption properties and ultrafast photonics applications of HfS3.

In this Letter, we focus on investigating the ultrafast photonics applications of two-layer HfS3 nanosheets. We prepared two-layer HfS3 nanosheets and carried out experiments to study their nonlinear saturable absorption properties. The results showed that the two-layer HfS3-based saturable absorber exhibited a modulation depth of 16.8%. Additionally, we conducted theoretical calculations using first principles to estimate the structural and electronic band properties of the two-layer HfS3 material. Furthermore, we utilized the two-layer HfS3 materials as SAs in an erbium-doped fiber cavity to generate mode-locked laser pulses. We measured a repetition frequency of 8.74 MHz, a pulse duration of 540 fs, and a signal-to-noise ratio of 77 dB. Overall, our findings demonstrate that the two-layer HfS3 material can serve as a reliable saturable absorber, possessing properties comparable to currently used two-dimensional materials. This expands the application fields of HfS3 materials and highlights their potential for advanced optoelectronic devices.

Integrated HBV DNA and cccDNA maintain transcriptional activity in intrahepatic HBsAg-positive patients with functional cure following PEG-IFN-based therapy.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroclearance marks regression of hepatitis B virus (HBV) infection. However, more than one-fifth of patients with functional cure following pegylated interferon-based therapy may experience HBsAg seroreversion. The mechanisms causing the HBV relapse remain unclear. AIM: To investigate the level and origin of HBV transcripts in patients with functional cure and their role in predicting relapse. METHODS: Liver tissue obtained from patients with functional cure, as well as uncured and treatment-naïve HBeAg-negative patients with chronic hepatitis B (CHB) were analysed for intrahepatic HBV markers. HBV capture and RNA sequencing were used to detect HBV integration and chimeric transcripts. RESULTS: Covalently closed circular DNA (cccDNA) levels and the proportion of HBsAg-positive hepatocytes in functionally cured patients were significantly lower than those in uncured and treatment-naïve HBeAg-negative patients. Integrated HBV DNA and chimeric transcripts declined in functionally cured patients compared to uncured patients. HBsAg-positive hepatocytes present in 25.5% of functionally cured patients, while intrahepatic HBV RNA remained in 72.2%. The levels of intrahepatic HBV RNA, integrated HBV DNA, and chimeric transcripts were higher in functionally cured patients with intrahepatic HBsAg than in those without. The residual intrahepatic HBsAg in functionally cured patients was mainly derived from transcriptionally active integrated HBV DNA; meanwhile, trace transcriptional activity of cccDNA could also remain. Two out of four functionally cured patients with intrahepatic HBsAg and trace active cccDNA experienced HBV relapse. CONCLUSION: Integrated HBV DNA and cccDNA maintain transcriptional activity and maybe involved in HBsAg seroreversion in intrahepatic HBsAg-positive patients with functional cure and linked to virological relapse.

InSb-based saturable absorbers for ultrafast photonic applications.

Sb-related III-V compounds have recently gained great research interest owing to their excellent optical and electrical characteristics, which provide many possibilities in photonics and electronics. This study investigated the application of InSb films in ultrafast photonics. An InSb film was fabricated on the tapered zone of a microfiber, and its saturation intensity, modulation depth, and non-saturable loss were determined as 119.8 MW cm-2, 23.5%, and 27.3%, respectively. The structure of the electronic band and density of states of InSb were theoretically calculated. Notably, mode-locked and Q-switched fiber lasers were realised by incorporating the InSb-microfiber device into two different Er-doped fiber cavities. In the Q-switching state, the narrowest pulse duration was measured as 1.756 µs with a maximum single-pulse energy of 221.95 nJ and a signal-to-noise ratio of 60 dB. In the mode-locking operation, ultrafast lasers with a high signal-to-noise ratio (70 dB), a pulse width as narrow as 265 fs and a repetition rate of 49.51 MHz were acquired. Besides, the second-harmonic mode-locked state was built with an output power of 13.22 mW. In comparison with the reported laser performance with 2D materials as saturable absorbers, the InSb-based mode-locked and Q-switched fiber lasers proposed herein exhibit better comprehensive performance.

Angular-Dependent THz Modulator with Hybrid Metal-Graphene Metastructures.

The coupling effects of surface plasmon resonance (SPR) from metamaterials induce variation in both the frequency and intensity of plasmonic modes. Here, we report an angular-dependent THz modulator with hybrid metal-graphene metastructures. The metastructures composed of the period gold split-rod arrays on top of a monolayer graphene, which show redshift modulation in the THz region with an increasing incident angle due to the strong out-of-plane magnetic flux introduced by the clockwise circular current at the oblique incidence. By utilizing graphene-based actively tunable conductor with ion-gel electrical gating, the THz transmission can be significantly modified. The modulation depth of the hybrid metal-graphene metastructure modulator can reach ~37.6% at 0.62 THz with a gate voltage of -3 V. The theoretical modeling of transmitted dependency on frequency and incident angle is demonstrated at different Fermi energies, which fits well with the experimental results. This hybrid device can offer a useful method for THz applications (such as angle sensors or angular-resolved spectroscopy), where angle-dependent modulation is needed.

Chromium oxide film for Q-switched and mode-locked pulse generation.

Chromium oxide (Cr2O3) is a promising material used in the applications such as photoelectrochemical devices, photocatalysis, magnetic random access memory, and gas sensors. But, its nonlinear optical characteristics and applications in ultrafast optics have not been studied yet. This study prepares a microfiber decorated with a Cr2O3 film via magnetron sputtering deposition and examines its nonlinear optical characteristics. The modulation depth and saturation intensity of this device are determined as 12.52% and 0.0176 MW/cm2. Meanwhile, the Cr2O3-microfiber is applied as a saturable absorber in an Er-doped fiber laser, and stable Q-switching and mode-locking laser pulses are successfully generated. In the Q-switched working state, the highest output power and shortest pulse width are measured as 12.8 mW and 1.385 µs, respectively. The pulse duration of this mode-locked fiber laser is as short as 334 fs, and its signal-to-noise ratio is 65 dB. As far as we know, this is the first illustration of using Cr2O3 in ultrafast photonics. The results confirm that Cr2O3 is a promising saturable absorber material and significantly extend the scope of saturable absorber materials for innovative fiber laser technologies.

Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation.

Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.

Direct Z-Scheme SnSe2/SnSe Heterostructure Passivated by Al2O3 for Highly Stable and Sensitive Photoelectrochemical Photodetectors.

To mimic the natural photosynthesis system, a Z-scheme heterostructure is proposed as a viable and effective strategy for efficient solar energy utilization such as photocatalysis and photoelectrochemical (PEC) water splitting due to the high carrier separation efficiency, fast charge transport, strong redox, and wide light absorption. However, it remains a huge challenge to form a direct Z-scheme heterostructure due to the internal electric-field restriction and vital band-alignment at the interface. Herein, the van der Waals heterostructure based on the allotrope SnSe2 and SnSe is designed and synthesized by a two-step vapor phase deposition method to overcome the limitation in the formation of the Z-scheme heterostructure for the first time. The Z-scheme heterostructure of SnSe2/SnSe is confirmed by X-ray photoelectron spectroscopy, ultraviolet photoelectron spectroscopy, PEC measurement, density functional theory calculations, and water splitting. Strikingly, the PEC photodetectors based on the Z-scheme heterostructure show a synergistic effect of superior stability from SnSe and fast photoresponse from SnSe2. As such, the SnSe2/SnSe Z-scheme heterostructure shows a good photodetection performance in the ultraviolet to visible wavelength range. Furthermore, the photodetector shows a faster response/recovery time of 13/14 ms, a higher photosensitivity of 529.13 µA/W, and a higher detectivity of 4.94 × 109 Jones at 475 nm compared with those of single components. Furthermore, the photodetection stability of the SnSe2/SnSe is also greatly improved by a-thin-Al2O3-layer passivation. The results imply the promising rational design of a direct Z-scheme heterostructure with efficient charge transfer for high performance of optoelectronic devices.

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid ß-Oxidation.

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid ß-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Lack of evolutionary convergence in multiple primary lung cancer suggests insufficient specificity of personalized therapy.

Multiple primary lung cancer (MPLC) is an increasingly prevalent subtype of lung cancer. According to recent genomic studies, the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence. We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found. Using our own and other relevant public data, evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk, indicating evolutionary contingency rather than adaptive convergence. Additionally, tumors from the same MPLC patient are as genetically diverse as those from different patients, while within-tumor genetic heterogeneity is significantly lower. Furthermore, the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor, but not with samples from other tumors or other patients. Overall, there is no evidence of adaptive convergence during the evolution of MPLC. Most importantly, the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient. To fully exploit the strategic value of precision medicine, targeted therapies should be designed and delivered on a per-lesion basis.

VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis.

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from the cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.

GaSb Film is a Saturable Absorber for Dissipative Soliton Generation in a Fiber Laser.

Nanotechnology is at the forefront of scientific research and offers great prospects for the development of technology. As a type of III-V semiconductor, GaSb materials exhibit numerous outstanding optical and electrical characteristics that are very promising for nonlinear optical device applications. In this study, the electronic band structures of GaSb are theoretically calculated, and its application in dissipative soliton fiber lasers is validated. A GaSb thin film is deposited on a microfiber using magnetron sputtering deposition, and the morphology, chemical composition, structure, and nonlinear optical characteristics of the proposed microfiber-GaSb device are investigated. After incorporating it into an Er-doped fiber laser, dissipative soliton laser pulses are readily obtained with a fundamental frequency of 43.5 MHz. With increasing pump power, the fiber laser could work in the fundamental frequency mode-locking state. At a pump power of 570 mW, the pulse width and the output power are measured to be 917 fs and 49.75 mW, separately. These results reveal that GaSb can be used as an efficient saturable absorber, which will have potential applications in ultrafast optics.

Non-Invasive Prediction Models for Esophageal Varices and Red Signs in Patients With Hepatitis B Virus-Related Liver Cirrhosis.

Background: Red signs are closely related to esophageal variceal bleeding, and, despite improvements in therapy, the mortality rate remains high. We aimed to identify non-invasive predictors of esophageal varices and red signs in patients with hepatitis B virus-related liver cirrhosis. Methods: This retrospective study included 356 patients with hepatitis B virus-related liver cirrhosis after applying inclusion and exclusion criteria among 661 patients. All patients underwent endoscopy, ultrasonography, laboratory examinations, and computed tomography/magnetic resonance imaging. Univariate and multivariate logistic regression analysis were performed, and prediction models for esophageal varices and red signs were constructed. Results: Multivariate analysis revealed that spleen diameter, splenic vein diameter, and lymphocyte ratio were independent risk factors for esophageal varices and red signs. On this basis, we proposed two models: i) a spleen diameter-splenic vein diameter-lymphocyte ratio-esophageal varices prediction model (SSL-EV model); and ii) a spleen diameter-splenic vein diameter-lymphocyte ratio-red sign prediction model (SSL-RS model). The areas under the receiver operating characteristic curve for the two prediction models were 0.843 and 0.783, respectively. With a cutoff value of 1.55, the first prediction model had 81.3% sensitivity and 76.1% specificity for esophageal varices prediction. With a cutoff value of -0.20, the second prediction model had 72.1% sensitivity and 70.7% specificity for the prediction of red signs. Conclusions: We proposed a new statistical model, the spleen diameter-splenic vein diameter-lymphocyte ratio-red sign prediction model (SSL-RS model), to predict the presence of red signs non-invasively. Combined with the spleen diameter-splenic vein diameter-lymphocyte ratio-esophageal varices prediction model (SSL-EV model), these non-invasive prediction models will be helpful in guiding clinical decision-making and preventing the occurrence of esophageal variceal bleeding.

Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.

Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.

Anomalous polarization pattern evolution of Raman modes in few-layer ReS2 by angle-resolved polarized Raman spectroscopy.

Low-symmetry of ReS2 has not only in-plane but also out-of-plane anisotropic light scattering, which is complicated, yet interesting with intrinsic strong electron-phonon coupling. In such a case, the Raman tensor also gets sophisticated with nine non-zero elements, which is layer-dependent for different Raman modes. Herein, we systematically investigated the polarization pattern evolution of both in-plane and out-of-plane Raman modes of few-layer ReS2 by angle-resolved polarized Raman spectroscopy. We found that in-plane Raman modes with less layer-dependence could be used to determine the crystal orientation (Re-chain direction) due to the weak electron-phonon interaction between layers. However, the out-of-plane and mixed vibration Raman modes demonstrate much evident layer-dependence due to the obvious electron-phonon interaction between layers. As such, the polarization patterns for the out-of-plane vibration Raman modes are distorted with layers in not only petal types but also maximum Raman intensity directions. This distortion is mainly due to the phase difference between Raman elements, which are complex values due to the near bandgap excitation laser. The results reveal that deep insights into anisotropy in low-symmetry two-dimensional materials could afford not only rich physics but also potential polarized optoelectronic devices.

Anisotropic Second-Harmonic Generation Induced by Reduction of In-Plane Symmetry in 2D Materials with Strain Engineering.

Strain engineering is an attractive method to induce and control anisotropy for polarized optoelectronic applications with two-dimensional (2D) materials. Herein, we have investigated the nonlinear optical coefficient dispersion relationship and the second-harmonic generation (SHG) pattern evolution under the uniaxial strains for graphene, WS2, GaSe, and In2Se3 monolayers. The uniaxial strain can break the in-plane symmetry of 2D materials, leading to both trade-off breaking of the nonlinear coefficient and new emergent nonlinear coefficients. In such a case, a classical sixfold ϕ-dependent SHG pattern is transformed into a distorted sixfold SHG pattern under the strain. Due to the lattice symmetry breaking and the uneven charge density distribution in strained 2D materials, the SHG patterns also depend on the excitation photon energy. The results could give a guide for the SHG pattern analysis in experiments, suggesting strain engineering on 2D materials for the tunable anisotropy in polarized and flexible nonlinear optical devices.

Layer-Dependent Nonlinear Optical Properties of WS2, MoS2, and Bi2S3 Films Synthesized by Chemical Vapor Deposition.

Two-dimensional (2D) layered materials have shown layer-dependent optical properties in both linear optical and nonlinear optical (NLO) regimes due to prominent interlayer coupling and quantum confinement in an atomic scale. However, the NLO properties become more complicated as both saturable absorption (SA) and reverse saturable absorption (RSA) easily happen in 2D materials, which results in a significant challenge to understand the evolution of nonlinear absorption with layers. Motivated by this, chemical vapor-deposited chalcogenide compounds (WS2, MoS2, and Bi2S3) are used to investigate the pump intensity and layer number-dependent NLO properties. The values of nonlinear absorption coefficients of these chalcogenide compounds increase with the pump intensity by an 800 nm femtosecond laser, which can be described by an empirical power law function. The SA process due to the large transition probability of the ground state readily takes place in thick samples, while RSA occurs easily in thin samples due to the two-photon absorption (TPA). The transition from TPA to SA is deduced to occur at 13L-WS2, 15L-MoS2, and 5L-Bi2S3, which is related to the layer-dependent band gaps. Our results provide an efficient way to tune optical nonlinearities with a controlled layer number and to design corresponding NLO devices such as optical switches and saturable absorbers.

Eosinophil extracellular traps drive asthma progression through neuro-immune signals.

Eosinophilic inflammation is a feature of allergic asthma. Despite mounting evidence showing that chromatin filaments released from neutrophils mediate various diseases, the understanding of extracellular DNA from eosinophils is limited. Here we show that eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid are associated with the severity of asthma in patients. Functionally, we find that EETs augment goblet-cell hyperplasia, mucus production, infiltration of inflammatory cells and expressions of type 2 cytokines in experimental non-infection-related asthma using both pharmaceutical and genetic approaches. Multiple clinically relevant allergens trigger EET formation at least partially via thymic stromal lymphopoietin in vivo. Mechanically, EETs activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, which is potentiated by eosinophil peroxidase. Subsequently, the pulmonary neuroendocrine cells amplify allergic immune responses via neuropeptides and neurotransmitters. Therapeutically, inhibition of CCDC25 alleviates allergic inflammation. Together, our findings demonstrate a previously unknown role of EETs in integrating immunological and neurological cues to drive asthma progression.

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate-limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.