B Cells and IL-21-Producing Follicular Helper T Cells Cooperate to Determine the Dynamic Alterations of Premetastatic Tumor Draining Lymph Nodes of Breast Cancer.

Metastasis is the major cause of cancer-related death, and lymph node is the most common site of metastasis in breast cancer. However, the alterations that happen in tumor-draining lymph nodes (TDLNs) to form a premetastatic microenvironment are largely unknown. Here, we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer. With the progression of tumor, the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis. The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized. Mechanistically, B and follicular helper T (Tfh) cells parallelly expand and contract to determine the size of TDLN. The activation status and specific antitumor immunity of CD8+ T cells in the TDLN are determined by interleukin-21 (IL-21) produced by Tfh cells, thus showing parallel changes. The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells. On the basis of the B-Tfh-IL-21-CD8+ T cell axis, we prove that targeting the axis could activate TDLNs to resist metastasis. Together, our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.

Greenhouse gas emission in the whole process of forest fire including rescue: a case of forest fire in Beibei District of Chongqing.

In the context of global high temperature, the harm of greenhouse gases (GHG) emissions caused by frequent forest fires to the environment cannot be ignored. Existing research only calculates the GHG generated by the burning of forest vegetation, ignoring the GHG generated by the fire-driven social rescue activities. Taking the forest fire in Beibei District, Chongqing City, China, as an example, this paper studies and establishes the GHG emission accounting method for the whole process of forest fire from ignition to fire extinguishing through three processes: vegetation burning, rescue transportation, and on-site fire extinguishing. It covers three GHG calculation types: biomass burning, traffic activity level comprehensive energy consumption, and machine energy consumption. Among them, the CO2 produced by the burning of coniferous forest, the support transportation of rescue teams in Yunnan province, and the motorcycle transportation at the fire extinguishing site accounted for a relatively high proportion in the corresponding processes, reaching 12,761.445 t, 118.750 t, and 1056.980 t, respectively. Finally, through data analysis, suggestions on GHG emission reduction related to forest tree regulation and optimization of rescue and fire extinguishing management are put forward, which provides a direction for future research on carbon reduction in the whole process of forest fire events.

Adeno-associated virus-9 reverses delayed gastric emptying of solids in diabetic mice.

BACKGROUND: Gastroparesis is defined by delayed gastric emptying (GE) without obstruction. Studies suggest targeting heme oxygenase-1 (HO1) may ameliorate diabetic gastroparesis. Upregulation of HO1 expression via interleukin-10 (IL-10) in the gastric muscularis propria is associated with reversal of delayed GE in diabetic NOD mice. IL-10 activates the M2 cytoprotective phenotype of macrophages and induces expression of HO1 protein. Here, we assess delivery of HO1 by recombinant adeno-associated viruses (AAVs) in diabetic mice with delayed GE. METHODS: C57BL6 diabetic delayed GE mice were injected with 1 × 1012 vg scAAV9-cre, scAAV9-GFP, or scAAV9-HO1 particles. Changes to GE were assessed weekly utilizing our [13 C]-octanoic acid breath test. Stomach tissue was collected to assess the effect of scAAV9 treatment on Kit, NOS1, and HO1 expression. KEY RESULTS: Delayed GE returned to normal within 2 weeks of treatment in 7/12 mice receiving scAAV9-cre and in 4/5 mice that received the scAAV9-GFP, whereas mice that received scAAV9-HO1 did not respond in the same manner and had GE that took significantly longer to return to normal (6/7 mice at 4-6 weeks). Kit, NOS1, and HO1 protein expression in scAAV9-GFP-treated mice with normal GE were not significantly different compared with diabetic mice with delayed GE. CONCLUSIONS AND INFERENCES: Injection of scAAV9 into diabetic C57BL6 mice produced a biological response that resulted in acceleration of GE independently of the cargo delivered by the AAV9 vector. Further research is needed to determine whether use of AAV mediated gene transduction in the gastric muscularis propria is beneficial and warranted.

Fluorescence turn-off sensing strategy based on Al-based MOF for selective detection of tricresyl phosphate.

Tricresyl phosphate (TCP), a notable emerging pollutant with a high bioconcentration factor and biotoxicity, is a typical representative of aryl-organophosphorus flame retardants. The electrochemical and chromatographic technologies used in conventional TCP detection have a variety of drawbacks. Hence, it is crucial to suggest an easy, accurate, and selective method for detecting TCP. In this study, we presented a brand-new method based on NH2-MIL-53(Al) nanoprobe for the direct luminescence assay of TCP. NH2-MIL-53(Al) possessed an excellent crystal structure and superior optical qualities. Notably, the introduction of TCP caused a considerable dampening of the photoluminescence signal of the nanoprobe. The fluorescence response based on static quenching was verified by fluorescence lifetime decay curves. The thermodynamic analysis further concluded that TCP and nanoprobe spontaneously produced non-fluorescent complexes due to hydrophobic interaction. The quenching efficiency (F0-F)/F0 of the nanoprobe and the TCP concentration displayed good linearity in the scope of 0.3-3.0 µM (R2 = 0.996), and the LOD was 0.058 µM under the ideal detection conditions. More significantly, the technique was effectively used to identify TCP in lake and tap water (RSD ≤5.79%), which provided a fresh perspective on how to recognize OPFRs in environmental water.

Ambient Electrosynthesis of Urea with Nitrate and Carbon Dioxide over Iron-Based Dual-Sites.

The development of efficient electrocatalysts to generate key *NH2 and *CO intermediates is crucial for ambient urea electrosynthesis with nitrate (NO3 - ) and carbon dioxide (CO2 ). Here we report a liquid-phase laser irradiation method to fabricate symbiotic graphitic carbon encapsulated amorphous iron and iron oxide nanoparticles on carbon nanotubes (Fe(a)@C-Fe3 O4 /CNTs). Fe(a)@C-Fe3 O4 /CNTs exhibits superior electrocatalytic activity toward urea synthesis using NO3 - and CO2 , affording a urea yield of 1341.3±112.6 µg h-1 mgcat -1 and a faradic efficiency of 16.5±6.1 % at ambient conditions. Both experimental and theoretical results indicate that the formed Fe(a)@C and Fe3 O4 on CNTs provide dual active sites for the adsorption and activation of NO3 - and CO2 , thus generating key *NH2 and *CO intermediates with lower energy barriers for urea formation. This work would be helpful for design and development of high-efficiency dual-site electrocatalysts for ambient urea synthesis.

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

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

Hierarchical WO3-x Ultrabroadband Absorbers and Photothermal Converters Grown from Femtosecond Laser-Induced Periodic Surface Structures.

Oxygen-vacancy-rich WO3-x absorbers are gaining increasing attention because of their extensive absorbance-based applications in near-infrared shielding, photocatalysis, sterilization, interfacial evaporator and electrochromic, photochromic, and photothermal fields. Thermal treatment in an oxygen-deficient atmosphere enables us to prepare WO3-x but lacks the capacity for finely manipulating the grown structures. In this work, we present that laser-induced periodic surface structure (LIPSS) obtained by femtosecond laser ablation is a good template to grow various hierarchical WO3-x ultrabroadband absorbers and photothermal converters by thermal oxidation annealing in air. Increasing annealing temperature from 600 to 1000 °C allows the manipulation of WO3-x crystal sizes from ∼70 nm to ∼4 µm, accompanied by a color transition from brown to dark blue and finally to yellow. Benefiting from annealing-induced surface cracks and phase transition into WO3-x (containing both WO3 and W18O49) at 600 °C, excellent UV-vis-NIR-MIR ultrabroadband absorbers were produced: >90% UV-NIR absorbance (0.3-2.5 µm) and 50-90% MIR absorbance (2.5-16 µm), much better than most W-based metamaterial absorbers. The higher the annealing temperature (1000 > 800 > 600 °C), the better the photothermal performances (sample temperature as the indicator) of annealed interfaces due to the increased oxidation rates and resultant thicker oxide layers (6, 150, and 507 µm), a trend which is more apparent upon the irradiation of high-density (3160 mW/cm2) and ultrabroadband (200-2500 nm) light but much less apparent for shorter-band (200-800, 420-800, 800-2500 nm, etc.) and less-intensity (1694, 1540, 1460 mW/cm2, etc.) light irradiation. This phenomenon indicates that (1) higher-performance ultrabroadband absorbers possess a higher photothermal conversion capacity; (2) thicker-WO3-x oxide layer converters are more effective in preserving photothermal heat; and (3) both the W-LIPSS and metal tungsten substrate can quickly dissipate the photothermal heat to inhibit heat accumulation in the oxide photothermal converters. It is also proved that ablation-induced high-pressure shockwaves can produce deformation layers in the subsurfaces to release annealing-induced stresses, beneficial for the formation of less-cracked non-stoichiometric WO3-x interfaces upon annealing. High-pressure shockwaves are also capable of inducing grain refinement of LIPSS, which facilitates a homogeneous growth of small non-stoichiometric metal-oxide crystals upon annealing. Our results indicate that femtosecond laser ablation is a convenient upstream template-fabrication technique compatible with the thermal oxidation annealing method to develop advanced functional oxygen-vacancy metal-oxide interfaces.

Surface morphology and payload synergistically caused an enhancement of the longitudinal relaxivity of a Mn3O4/PtOx nanocomposite for magnetic resonance tumor imaging.

The construction of surface structures of manganese oxide nanoparticles (MONs) in order to promote their longitudinal relaxivity r1 to surpass those of commercially available Gd(iii) complexes is still a significant challenge. Herein, we successfully obtained Mn3O4/PtOx nanocomposites (NCs) with an r1 of 20.48 mM-1 s-1, four times higher than that of commercially available Gd-DTPA (5.11 mM-1 s-1). The r2/r1 ratio of these NCs is 1.46 lower than that of Gd-DTPA (2.38). This is the first time that such excellent T1 contrast performance has been achieved using MONs via synergistically utilizing the surface morphology and surface payload. These NCs are composed of porous Mn3O4"skeleton" nanostructures decorated with tiny PtOx nanoparticles (NPs) that are realized using laser ablation and irradiation in liquid and ion etching steps. Experimental results showed that the enlarged specific area of the porous Mn3O4/PtOx NCs and the payload of ultrafine PtOx NPs synergistically facilitated the T1 contrast capabilities. The former favors sufficient proton-electron interactions and the latter reduces the global molecular tumbling motion. These NCs also exhibit an evident computed tomography (CT) attenuation value of 24.13 HU L g-1, which is much better than that achieved using the commercial product iopromide (15.9 HU L g-1). The outstanding magnetic resonance (MR) imaging and CT imaging performances of the Mn3O4/PtOx NCs were proved through in vivo experiments. Histological examinations and blood circulation assays confirmed the good biosafety of the NCs. These novel findings showcase a brand-new strategy for fabricating excellent MON T1 contrast agents (CAs) on the basis of the surface structure and they pave the way for their practical clinical applications in dual-modal imaging.

Platypnea-Orthodeoxia Syndrome: Rare or Under-Diagnosed Syndrome? 3 Case Reports and a Literature Review.

Platypnea-Orthodeoxia Syndrome (POS) is dyspnea and hypoxemia in the upright position that improves in the supine position. Cardiac POS is predominantly caused by congenital interatrial communications (CIC) paired with changes in the thoracic anatomy, allowing orthostatic right to left cardiac shunting. High suspicion, especially with hypoxemia without significant pulmonary disease, that does not easily correct with supplemental oxygen, should lead the clinician to obtain echocardiographic imaging, documenting right to left shunting, typically through a patent foramen ovale (PFO). Transcatheter closure of the CIC is highly successful in relieving symptoms of dyspnea and resolving hypoxemia in the majority of patients.

Muscularis macrophages establish cell-to-cell contacts with telocytes/PDGFRα-positive cells and smooth muscle cells in the human and mouse gastrointestinal tract.

BACKGROUND AND AIM: Muscularis macrophages (MMs) not only mediate the innate immunity, but also functionally interact with cells important for gastrointestinal motility. The aim of this study was to determine the spatial relationship and types of contacts between the MMs and neighboring cells in the muscularis propria of human and mouse stomach, small intestine, and large intestine. METHODS: The distribution and morphology of MMs and their contacts with other cells were investigated by immunohistochemistry and transmission electron microscopy. KEY RESULTS: Immunohistochemistry showed variable shape and number of MMs according to their location in different portions of the muscle coat. By double labeling, a close association between MMs and neighboring cells, that is, neurons, smooth muscle cells, interstitial cells of Cajal (ICCs), telocytes (TCs)/PDGFRα-positive cells, was seen. Electron microscopy demonstrated that in the muscle layers of both animal species, MMs have similar ultrastructural features and have specialized cell-to-cell contacts with smooth muscle cells and TCs/PDGFRα-positive cells but not with ICCs and enteric neurons. CONCLUSION & INFERENCES: This study describes varying patterns of distribution of MMs between different regions of the gut, and reports the presence of distinct and extended cell-to-cell contacts between MMs and smooth muscle cells and between MMs and TCs/PDGFRα-positive cells. In contrast, MMs, although close to ICCs and nerve elements, did not make contact with them. These findings indicate specialized and variable roles for MMs in the modulation of gastrointestinal motility whose significance should be more closely investigated in normal and pathological conditions.

Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3.

Previous circular RNA (circRNA) microarray analyses have uncovered an abnormal expression of hsa_circ_0070963 in hepatic stellate cells (HSCs). However, the specific role of hsa_circ_0070963 in liver fibrosis remains unknown. Here, we show that hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. Moreover, we demonstrated that hsa_circ_0070963 levels were reduced during liver fibrosis while restoring hsa_circ_0070963 levels abolished HSC activation, with a reduction in α-SMA and type I collagen levels both in vitro and in vivo. Furthermore, hsa_circ_0070963 overexpression suppressed both cell proliferation and the cell cycle of HSCs. MiR-223-3p was confirmed as a target of hsa_circ_0070963 and was shown to be involved in the effects of hsa_circ_0070963 on HSC activation. Furthermore, LEMD3 was confirmed as a target of miR-223-3p and was shown to be responsible for the activation of HSCs. The interactions between hsa_circ_0070963, miR-223-3p, and LEMD3 were validated via bioinformatic analysis, luciferase reporter assays, and rescue experiments. Collectively, hsa_circ_0070963 appeared to function as a miR-223-3p sponge that inhibited HSC activation in liver fibrosis via regulation of miR-223-3p and LEMD3. Therefore, hsa_circ_0070963 may serve as a potential therapeutic target for liver fibrosis.

Laser ablation in liquids for the assembly of Se@Au chain-oligomers with long-term stability for photothermal inhibition of tumor cells.

For the potential use of Au nanoparticles (NPs) in photothermal therapy, it is important and effective to achieve the uniaxial assembly of Au NPs to allow enhanced absorption in the near infrared (NIR) region. Herein, we first presented the construction of amorphous selenium encapsulated gold (Se@Au) chain-oligomers by successive laser ablation of Au and Se targets in sodium chloride solution without other toxic precursors, stabilizers, or templating molecules. Se@Au chain-oligomers showed evidently enhanced NIR absorption and excellent photothermal transduction efficiency (η), which was higher than 47% at 808 nm. After being stored for 1 year, the Se@Au colloids still exhibited outstanding photothermal performance. The cytotoxicity assay demonstrated that there is negligible toxicity of Se@Au chain-oligomers in cells, but cell viability declined to only 1% in phototherapeutic experiments that were implemented in vitro. In intracellular Reactive Oxygen Species (ROS) generation measurements, Se@Au chain-oligomers could trigger a 35.9% increment of ROS upon laser irradiation. The possible synergetic effects between the anticancer function of Se and photothermal behaviors of Se@Au oligomers were intended to increase ROS level in cells. Therefore, such designed Se@Au chain-oligomers of high stability exhibit promising potential for their use as in vivo photothermal therapeutic agents.

Effects of Neuropeptide Substance P on Proliferation and ß-Cell Differentiation of Adult Pancreatic Ductal Cells.

Purpose: The pancreas is innervated by sensory nerves, parasympathetic and sympathetic nerves. The classical neurotransmitters, acetylcholine and noradrenaline, and some kind of neuropeptides are contained in the terminals of these nerves. Neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) co-released from the primary sensory fibers have been identified as the key neurotransmitters in pancreas. Pancreatic ductal epithelium cells are one of the important sources of the pancreatic islet ß-cell neogenesis. We hypothesized that SP and CGRP might play a role on proliferation of ductal cells and differentiation of ductal cells toward the ß-cell neogenesis. Methods: Primary ductal cells of rat pancreas at the third passage (P3) were used. The identification of P3 cells were confirmed with flow cytometry analysis and immunostaining by CK19 (the ductal cell marker). Proliferation of ductal cells was verified by CCK-8 assay and Ki67 immunostaining. Differentiation of ductal cells was determined with immunostaining and flow cytometry. Possible mechanism was explored by testing the key proteins of Wnt signaling using Western blot analysis. Results: Our data showed that SP but not CGRP promoted proliferation of ductal cells. Moreover, NK-1 receptor antagonist L-703,606 blocked the SP-induced stimulation of proliferation. The results of Western blot analysis showed that L-703,606 attenuated the effects of substance P on NK1R, GSK-3ß, and ß-catenin expression. However, SP did not directly induce the differentiation of ductal cells into ß-cells, and did not promote the progression of ductal cells to differentiate into more insulin-produced cells in induction medium. Conclusions: These findings suggested that SP but not CGRP promoted proliferation of adult pancreatic ductal cells. SP promoted proliferation of ductal cells but not differentiation into ß-cells. NK1R and Wnt signaling pathway might be involved in the mechanism of promoting the proliferation of ductal cells by SP. Findings in this study indicated the lack of SP might be a possible indicator for the initial of diabetes. SP could also be used as a drug candidate for the treatment of diabetes.