LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.

Neuronal PER-ARNT-SIM (PAS) domain protein 4 (NPAS4) is a protective transcriptional regulator whose dysfunction has been linked to a variety of neuropsychiatric and metabolic diseases. As a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor family, NPAS4 is distinguished by an ability to form functional heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT) and ARNT2, both of which are also bHLH-PAS family members. Here, we describe the quaternary architectures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers in complexes involving DNA response elements. Our crystallographic studies reveal a uniquely interconnected domain conformation for the NPAS4 protein itself, as well as its differentially configured heterodimeric arrangements with both ARNT and ARNT2. Notably, the PAS-A domains of ARNT and ARNT2 exhibit variable conformations within these two heterodimers. The ARNT PAS-A domain also forms a set of interfaces with the PAS-A and PAS-B domains of NPAS4, different from those previously noted in ARNT heterodimers formed with other class I bHLH-PAS family proteins. Our structural observations together with biochemical and cell-based interrogations of these NPAS4 heterodimers provide molecular glimpses of the NPAS4 protein architecture and extend the known repertoire of heterodimerization patterns within the bHLH-PAS family. The PAS-B domains of NPAS4, ARNT, and ARNT2 all contain ligand-accessible pockets with appropriate volumes required for small-molecule binding. Given NPAS4's linkage to human diseases, the direct visualization of these PAS domains and the further understanding of their relative positioning and interconnections within the NPAS4-ARNT and NPAS4-ARNT2 heterodimers may provide a road map for therapeutic discovery targeting these complexes.

Fast wavelength-swept polarization maintaining all-fiber mode-locked laser based on a piezo-stretched fiber Lyot filter.

We demonstrate for the first time a strain-controlled all polarization-maintaining (PM) fiber Lyot filter based on a piezoelectric lead zirconate titanate (PZT) fiber stretcher. This filter is implemented in an all-PM mode-locked fiber laser to serve as a novel wavelength-tuning mechanism for fast wavelength sweeping. The center wavelength of the output laser can be tuned across a range from 1540 nm to 1567 nm linearly. And the strain sensitivity achieved in the proposed all-PM fiber Lyot filter is 0.052nm/µÎµ, which is 43 times higher than that achievable by other strain-controlled filters such as a fiber Bragg grating filter (0.0012nm/µÎµ). Wavelength-swept rates up to 500 Hz and wavelength tuning speeds up to 13,000 nm/s are demonstrated, which is hundreds of times faster than what is attainable with conventional sub-picosecond mode-locked lasers based on mechanical tuning methods. This highly repeatable and swift wavelength-tunable all-PM fiber mode-locked laser is a promising source for applications requiring fast wavelength tunability, such as coherent Raman microscopy.

All-polarization-maintaining, efficiently wavelength-tunable, Er-doped mode-locked fiber laser with a compact reflective Lyot filter.

Wavelength tunable mode-locked fiber lasers have highly potential applications in precision spectroscopy, nonlinear microscopy and photonic sensing. Here, we present a compact and thermal-sensitive reflective Lyot filter and utilize it for all-polarization-maintaining efficiently wavelength-tunable Er-doped carbon-nanotube-mode-locked laser for the first time, to the best of our knowledge. The output wavelength of the laser can be tuned from 1544.46 nm to 1572.71 nm, with a wide tuning range of 28.25 nm, and a remarkable tuning efficiency of 0.589 nm/°C, when the angle-spliced fiber is only 8.2 cm and the free spectral range of the filter is 31.32 nm. Dual-wavelength mode-locking is also achieved at boundary temperatures when increasing the pump power. Due to its compact size and reflection configuration, the proposed reflective Lyot filter is promising for realizing highly efficient wavelength tuning and multiwavelength generation in all-polarization-maintaining fiber lasers where reflective filters are needed.

Recent Advances in Organic Photovoltaic Materials Based on Thiazole-Containing Heterocycles.

Organic solar cells (OSCs) have achieved great progress, driven by the rapid development of wide bandgap electron donors and narrow bandgap non-fullerene acceptors (NFAs). Among a large number of electron-accepting (A) building blocks, thiazole (Tz) and its derived fused heterocycles have been widely used to construct photovoltaic materials, especially conjugated polymers. Benefiting from the electron deficiency, rigidity, high planarity, and enhanced intra/intermolecular interactions of Tz-containing heterocycles, some related photovoltaic materials exhibit proper energy levels, optimized molecular aggregation, and active layer morphology, leading to excellent photovoltaic performance. This review focuses on the progress of Tz-based photovoltaic materials in the field of OSCs. First, the Tz-based donor and acceptor photovoltaic materials are reviewed. Then, the materials based on promising Tz-containing heterocycles, mainly including thiazolo[5,4-d]thiazole (TzTz), benzo[1,2-d:4,5-d']bis(thiazole) (BBTz), and benzo[d]thiazole (BTz) are summarized and discussed. In addition, the new emerging Tz-fused structures and their application in OSCs are introduced. Finally, perspectives and outlooks for the further development of Tz-containing heterocycle-based photovoltaic materials are proposed.

Room-Temperature Spin Transport in Metal Nanocluster-Based Spin Valves.

As a new type of inorganic-organic hybrid semiconductor, quantum-confined atomically precise metal nanoclusters (MNCs) have been widely applied in the fields of chemical sensing, optical imaging, biomedicine and catalysis. Herein, we successfully design and fabricate the first example of MNC-based spin valves (SVs) that exhibit remarkable magnetoresistance (MR) value up to 1.6 % even at room temperature (300 K). The concomitant photoresponse of MNC-based SVs unambiguously confirms that the spin-polarized electron transmission takes place across the MNC interlayer. Furthermore, the spin-dependent transport property of MNC-based SVs is largely varied by changing the atomic structure of MNCs. Both experimental proofs and quantum chemistry calculations reveal that the atomic structure-discriminative spin transport behavior is attributed to the distinct spin-orbit coupling (SOC) effect of MNCs.

Polarization-maintaining all-fiber tunable mode-locked laser based on a thermally controlled Lyot filter.

We propose and demonstrate for the first time, to the best of our knowledge, a thermally controlled all polarization-maintaining (PM) fiber Lyot filter. This filter is implemented in an all-PM mode-locked fiber laser to achieve wavelength tunability. When operating in the single-wavelength tunable mode, the center wavelength can be tuned across a range from 1546 nm to 1571 nm. Furthermore, the laser can also operate in a dual-wavelength mode with center wavelengths at 1545 nm and 1571 nm. The temperature sensitivity achieved in our all-PM fiber Lyot filter is 0.602 nm/°C, which is over 46 times higher than other fiber-based filters such as a fiber Bragg grating filter (0.013 nm/°C). This highly stable and versatile wavelength-tunable all-PM fiber mode-locked laser is a promising source for various applications requiring wavelength tunability and/or dual-wavelength output, such as coherent Raman microscopy and dual-comb spectroscopy.

A novel energy level detector for molecular semiconductors.

The multifunction of molecule-based devices is always achieved by improving their charge transport characteristics. These characteristics depend strongly on the energy levels of molecular semiconductors, which fundamentally govern the working principle and device performance. Therefore, an accurate measurement of these energy levels is crucial for evaluating the availability of the prepared materials and thus optimizing the device performance. Here, an easy-to-operate three-terminal hot electron transistor has been developed, which comprises a molecular optoelectronic device that records the charge transport. It achieves exceptional properties including the lowest unoccupied molecular orbit level, highest occupied molecular orbit level, higher energy states, and higher electronic bandgap. When compared with existing techniques such as cyclic voltammetry, inverse photoemission spectroscopy, and ultraviolet photoemission spectroscopy, the hot electron transistor provides in-situ characterization and categorizes the measured energy information as intrinsic properties of the molecular semiconductor. Furthermore, we provide an in-depth understanding of the fundamental device-physics, which provides promising guidance for performance optimization.

Electron-deficient TVT unit-based D-A polymer donor for high-efficiency thick-film OSCs.

As the power conversion efficiencies of organic solar cells (OSCs) have been improved continuously in recent years, more attention will be paid to the industrial production and practical application of OSCs. However, there are still many problems to be solved in the process of large-scale production. Among them, reducing the costs of the materials and enhancing the film-thickness tolerance of the active layer are the two key points. Therefore, it is urgent to develop organic semiconductor materials which are easy to synthesize and suitable for the construction of high-efficiency, thick-film OSCs. In this work, we have focused on the (E)-2-[2-(thiophen-2-yl)vinyl]thiophene (TVT) unit because of its unique coplanar structure. And we noticed that TVT was mostly used as an electron-donating unit in the previous reports. However, we have modified TVT into electron-withdrawing unit by the introduction of fluorine atoms/ester groups. And two new donor-acceptor (D-A) copolymers have been obtained by combining the electron-withdrawing TVT unit with benzo[2,1-b:4,5-b']dithiophene (BDT) unit. Among them, the polymer based on the ester modified TVT unit presents excellent photovoltaic performance by virtue of its good solubility and preferable molecular stacking mode, and the corresponding devices also show extraordinarily high-thickness tolerance. The emergence of this new electron-withdrawing TVT unit will undoubtedly further promote the development of low-cost, high-efficiency, thick-film OSCs.

Fiber-based dynamically tunable Lyot filter for dual-wavelength and tunable single-wavelength mode-locking of fiber lasers.

We propose and demonstrate a novel dynamically tunable fiber-based Lyot filter for the realization of a dual-wavelength mode-locked fiber laser, operating at center wavelengths of 1535 nm and 1564 nm. The same laser cavity can also be operated in a single-wavelength mode-locked regime with a wavelength tuning range of 30 nm, from 1532 nm to 1562 nm. The proposed dynamically tunable Lyot-filter provides a simple setup for laser mode-locking using a single laser cavity design to generate dual-wavelength pulses, with the flexibility to also allow the generation of single-wavelength pulses with a continuously-tunable center wavelength.

Bis(triisopropylsilylethynyl)-substituted pyrene-fused tetraazaheptacene: synthesis and properties.

The synthesis and characterisation of a pyrene-fused tetraazaheptacene that is constituted of two terminal pyrene units and a central tetraazaanthracene core are reported. The optoelectronic properties (experimental and calculated) of this heptacene derivative are discussed together with its charge transport properties in thin films.

Expression of glucocorticoid receptor isoforms and associations with serine/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the expression of glucocorticoid receptor (GR) isoforms in patients with systemic lupus erythematosus (SLE), confirm the main GR isoforms involving in glucocorticoids (GC) resistance, and explore the associations of GR isoforms with serine/arginine-rich protein (SRp) 30c and SRp40. METHODS: Seventy patients with SLE and thirty-eight age- and sex-matched controls were recruited. All patients received prednisone (0.5-1 mg/kg/d) as their routine therapy. According to the therapeutic effect, patients were divided into glucocorticoid-resistant (GCR) and glucocorticoid-sensitive (GCS) groups. Transcript levels of GRα, GRß, GRγ, GR-P, SRp30c and SRp40 in peripheral blood mononuclear cells (PBMCs) were determined by real-time PCR. GRα and GRß proteins were detected by western blotting. Trial registration number is ChiCTR-RCH-12002808. RESULTS: Four GR transcripts in SLE patients showed the following trend: GRα (51.85%) > GR-P (23.78%) > GRγ (13.08%) >GRß (0.03%). GR-P transcript and ratio of GRα/GR-P in SLE patients were significantly higher than that in controls (p<0.05). GRα transcript and protein as well as SRp40 transcript in GCS group were significantly higher than that in the GCR group before GC treatment (p<0.05). In the GCS group, GRα transcript and SRp40 transcript were significantly higher after GC treatment than that before GC treatment (p<0.05). In the GCR group, GR-P transcript was significantly higher after GC treatment than that before GC treatment (p<0.05). Positive correlation between SRp40 and GRα transcript was found (p<0.05). Additionally, SLE Disease Activity Index scores were significantly negatively correlated with GRα transcript and protein expression (p<0.05). CONCLUSIONS: Our data demonstrated that the decreased expression of GRα might be the evidence of high disease activity and help to predict GC resistance. GR-P isoform might be implicated in the development of resistance. Additionally, the preliminary finding suggested that SRp40 might be associated with GRα transcripts in SLE patients.

Elevated serum leptin levels in patients with systemic lupus erythematosus.

Previous studies have indicated that leptin and the soluble leptin receptor (SLR) might influence inflammatory and immune processes in autoimmune diseases, but this remains unclear in systemic lupus erythematosus (SLE). The aim of our study was to assess if leptin and SLR are involved in the etiopathology of SLE and the possible mechanism of immune regulation. We studied 87 patients with SLE and 85 matched subjects. We assessed the levels of serum leptin and SLR, tested the long isoform leptin receptor (Ob-Rb) mRNA levels in SLE patients and a control group. Furthermore, we measured Th1 and Th2 percentage in SLE patients' lymphocytes and examined lymphocytes activation and proliferation assays with leptin stimulation in vitro. The study found a higher level of serum leptin in SLE patients, however, no difference was found in serum SLR levels or Ob-Rb mRNA levels between SLE patients and the control group. The percentage of Th1 cells decreased and Th2 cells increased after treatment with glucocorticoids in SLE patients. Leptin stimulated the proliferation of T cells in vitro, and differentiation to Th1 cells increased. The present study demonstrated that leptin may play an important role in the pathogenesis of SLE, inducing dysfunction of autoimmune processes.

[The relationship between mRNA level of glucocorticoid receptor α, heat shock protein 90, protein level of macrophage migration inhibitory factor and glucocorticoid resistance in systemic lupus erythematosus].

OBJECTIVE: To investigate the mRNA level of glucocorticoid receptor α (GRα) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance. METHODS: One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study. Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction. Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF. The association between these parameters and GC resistance was analyzed by Spearman correlation analysis. The multivariate logistic regression model was used to analyze the risk factors for GC resistance. RESULTS: The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18 (3.12, 17.20) vs 16.83 (12.01, 24.18), P=0.001; 18.46 (14.77, 26.45) vs 25.84 (17.97, 35.90), P= 0.005]. MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21±7.98) µg/L vs (18.34±6.29) µg/L; P=0.013]. The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84, 28.32) vs 26.64 (23.61, 47.16); P=0.001], as well as HSP90/GRα ratio (P=0.008). Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r=-0.275, P=0.004) and HSP90/GRα ratio (r=-0.341, P<0.001). SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23±2.86) µg/L vs (9.63±3.48) µg/L; P=0.003]. Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR=17.481, 95% CI 1.747-174.903, P=0.015). CONCLUSIONS: Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance. Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/Grα. Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.

Metagenomic next-generation sequencing on bronchoalveolar lavage fluid to contribute to diagnosis of subclinical pulmonary tuberculosis with scarce sputum and negative smear in a patient mimicking adult- onset still's disease: A case report.

Extremely high serum ferritin, which is regarded as a marker of adult-onset still's disease (AOSD), has been rarely observed in patients with TB. We report a case of TB diagnose by metagenomic next-generation sequencing(mNGS) who presented with clinical criteria of AOSD and extreme hyperferritinemia, which posed a diagnostic confusion. TB presenting with major clinical criteria of AOSD should be notable. Since TB remains a potentially curable disease, an awareness of its' protean manifestations is essential. A typical or even normal outcomes of clinical, microbiochemical, and radiologic evaluation should not be overlooked and dedicated diagnostic work-up should be performed for TB diagnosis. For equivocal cases, mNGS could be helpful.

Structural Isomeric Effect on Spin Transport in Molecular Semiconductors.

Molecular semiconductor (MSC) is a promising candidate for spintronic applications benefiting from its long spin lifetime caused by light elemental-composition essence and thus weak spin-orbit coupling (SOC). According to current knowledge, the SOC effect, normally dominated by the elemental composition, is the main spin-relaxation causation in MSCs, and thus the molecular structure-induced SOC change is one of the most concerned issues. In theoretical study, molecular isomerism, a most prototype phenomenon, has long been considered to possess little difference on spin transport previously, since elemental compositions of isomers are totally the same. However, here in this study, quite different spin-transport performances are demonstrated in ITIC and its structural isomers BDTIC experimentally, for the first time, though the charge transport and molecular stacking of the two films are very similar. By further experiments of electron-paramagnetic resonance and density-functional-theory calculations, it is revealed that noncovalent-conformational locks (NCLs) formed in BDTIC can lead to enhancement of SOC and thus decrease the spin lifetime. Hence, this study suggests the influences from the structural-isomeric effect must be considered for developing highly efficient spin-transport MSCs, which also provides a reliable theoretical basis for solving the great challenge of quantificational measurement of NCLs in films in the future.

Two natural compounds as potential inhibitors against the Helicobacter pylori and Acinetobacter baumannii IspD enzymes.

In a vast majority of bacteria, protozoa and plants, the methylerythritol phosphate (MEP) pathway is utilized for the synthesis of isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), which are precursors for isoprenoids. Isoprenoids, such as cholesterol and coenzyme Q, play a variety of crucial roles in physiological activities, including cell-membrane formation, protein degradation, cell apoptosis, and transcription regulation. In contrast, humans employ the mevalonate (MVA) pathway for the production of IDP and DMADP, rendering proteins in the MEP pathway appealing targets for antimicrobial agents. This pathway consists of seven consecutive enzymatic reactions, of which 4-diphosphocytidyl-2C-methyl-D-erythritol synthase (IspD) and 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) catalyze the third and fifth steps, respectively. In this study, we characterized the enzymatic activities and protein structures of Helicobacter pylori IspDF and Acinetobacter baumannii IspD. Then, using the direct interaction-based thermal shift assay, we conducted a compound screening of an approved drug library and identified 27 hit compounds potentially binding to AbIspD. Among them, two natural products, rosmarinic acid and tanshinone IIA sodium sulfonate, exhibited inhibitory activities against HpIspDF and AbIspD, by competing with one of the substrates, MEP. Moreover, tanshinone IIA sodium sulfonate also demonstrated certain antibacterial effects against H. pylori. In summary, we identified two IspD inhibitors from approved ingredients, broadening the scope for antibiotic discovery targeting the MEP pathway.

Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.

Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-XL, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

Strain-restricted transfer of ferromagnetic electrodes for constructing reproducibly superior-quality spintronic devices.

Spintronic device is the fundamental platform for spin-related academic and practical studies. However, conventional techniques with energetic deposition or boorish transfer of ferromagnetic metal inevitably introduce uncontrollable damage and undesired contamination in various spin-transport-channel materials, leading to partially attenuated and widely distributed spintronic device performances. These issues will eventually confuse the conclusions of academic studies and limit the practical applications of spintronics. Here we propose a polymer-assistant strain-restricted transfer technique that allows perfectly transferring the pre-patterned ferromagnetic electrodes onto channel materials without any damage and change on the properties of magnetism, interface, and channel. This technique is found productive for pursuing superior-quality spintronic devices with high controllability and reproducibility. It can also apply to various-kind (organic, inorganic, organic-inorganic hybrid, or carbon-based) and diverse-morphology (smooth, rough, even discontinuous) channel materials. This technique can be very useful for reliable device construction and will facilitate the technological transition of spintronic study.

Strategies and applications of generating spin polarization in organic semiconductors.

The advent of spintronics has undoubtedly revolutionized data storage, processing, and sensing applications. Organic semiconductors (OSCs), characterized by long spin relaxation times (>µs) and abundant spin-dependent properties, have emerged as promising materials for advanced spintronic applications. To successfully implement spin-related functions in organic spintronic devices, the four fundamental processes of spin generation, transport, manipulation, and detection form the main building blocks and are commonly in demand. Thereinto, the effective generation of spin polarization in OSCs is a precondition, but in practice, this has not been an easy task. In this context, considerable efforts have been made on this topic, covering novel materials systems, spin-dependent theories, and device fabrication technologies. In this review, we underline recent advances in external spin injection and organic property-induced spin polarization, according to the distinction between the sources of spin polarization. We focused mainly on summarizing and discussing both the physical mechanism and representative research on spin generation in OSCs, especially for various spin injection methods, organic magnetic materials, the chiral-induced spin selectivity effect, and the spinterface effect. Finally, the challenges and prospects that allow this topic to continue to be dynamic were outlined.