Interaction between systemic iron parameters and left ventricular structure and function in the preserved ejection fraction population: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Left ventricular (LV) remodeling and diastolic function in people with heart failure (HF) are correlated with iron status; however, the causality is uncertain. This Mendelian randomization (MR) study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population. METHODS: Transferrin saturation (TSAT), total iron binding capacity (TIBC), and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies. Individuals without myocardial infarction history, HF, or LV ejection fraction (LVEF) < 50% (n = 16,923) in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset. The dataset included LV end-diastolic volume, LV end-systolic volume, LV mass (LVM), and LVM-to-end-diastolic volume ratio (LVMVR). We used a two-sample bidirectional MR study with inverse variance weighting (IVW) as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results. RESULTS: In the IVW analysis, one standard deviation (SD) increased in TSAT significantly correlated with decreased LVMVR (ß = -0.1365; 95% confidence interval [CI]: -0.2092 to -0.0638; P = 0.0002) after Bonferroni adjustment. Conversely, no significant relationships were observed between other iron and LV parameters. After Bonferroni correction, reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT (ß = -0.0699; 95% CI: -0.1087 to -0.0311; P = 0.0004). No heterogeneity or pleiotropic effects evidence was observed in the analysis. CONCLUSIONS: We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.

Multi-functional device: manipulating linear and circular-polarization conversion in a terahertz chiral metamaterial.

We propose a terahertz chiral metamaterial as a multi-functional device to manipulate asymmetry transmission of linear polarized waves, linear-to-elliptical polarization conversion and circular dichroism in transmission mode while asymmetry reflection of circular polarized waves. For incidence of linear polarized waves, dual-band asymmetry transmission is shown around 0.42 THz and 1.04 THz where asymmetry transmission factors reach up to two peak values: ∼0.51 and ∼0.55, respectively. Intense linear-to-elliptical polarization conversion occurs at 0.81 THz and 0.97 THz, respectively. For incidence of circular polarized waves, a strong circular dichroism appears at 0.36 THz where circular dichroism parameter reaches to ∼0.64 and asymmetry reflection is displayed around 0.36 THz with the maximum of asymmetry reflection factors approaching to 0.55.

Generation of whole tumor cell vaccine for on-demand manipulation of immune responses against cancer under near-infrared laser irradiation.

The therapeutic efficacy of whole tumor cell vaccines (TCVs) is modest, which has delayed their translation into personalized immunotherapies in the clinic. Here, we develop a TCV platform based on photothermal nanoparticle-loaded tumor cells, which can be rationally applied to diverse tumor types to achieve on-demand boost of anti-tumor immune responses for inhibiting tumor growth. During the fabrication process, mild photothermal heating by near-infrared (NIR) laser irradiation induces the nanoparticle-bearing tumor cells to express heat shock proteins as endogenous adjuvants. After a single vaccination at the back of tumor-bearing mice, non-invasive NIR laser irradiation further induces mild hyperthermia at vaccination site, which promotes the recruitment, activation, and antigen presentation by dendritic cells. Using an indicator we term fluctuation of tumor growth rate, we determine appropriate irradiation regimens (including optimized irradiation intervals and times). This TCV platform enables on-demand NIR manipulation of immune responses, and we demonstrate potent therapeutic efficacy against six murine models that mimick a range of clinical scenarios, including a model based on humanized mice and patient-derived tumor xenografts.

Enhancement from Anaerobic Digestion of Food Waste by Conductive Materials: Performance and Mechanism.

Conductive materials (CM) have recently attracted research interest in the anaerobic digestion of food waste to achieve reduction and resource utilization. Fe-metal organic frameworks (Fe-MOF) and Ketjen Black (KB), the conductive materials (CMs), were added for the enhancement of food waste digestion. This study therefore, is intended to fill in this knowledge gap and clarify the underlying mechanism of CM-promoted performance. Batch experiments revealed that the optimal additions of Fe-MOF and KB were 0.5 g·L-1 and 0.2 g·L-1, respectively. The biogas production increased by 27.50% and 29.45% compared with the blank group, and the removal efficiency of volatile solids (VS), total solids (TS), and chemical oxygen demand (COD) increased by 18.28%, 40.52%, and 15.31%. The lag period was shortened from 3.042 to 2.006 and 1.544 days, respectively. Mechanism studies revealed that Fe-MOF and KB were beneficial to food waste digestion, and the functional groups of Fe-MOF and KB increased the buffer capacity of the system to pH and ammonia nitrogen. The physicochemical properties of Fe-MOF and KB promote the activity of the electron transfer system (ETS); the ETS activity was about 2 times the 11.32 mg·(g·h)-1 of the blank group. Zeta potential and electrical conductivity were beneficial to the establishment of intermicrobial direct interspecies electron transfer (DIET).

Endoscopic management of biliary ascariasis: A case report.

BACKGROUND: Biliary ascariasis is rare but remains the most common parasitic infection in remote areas and in people with poor medical conditions. Here, we reported a case of biliary ascariasis in order to raise awareness of possible parasitic infections. CASE SUMMARY: A 68-year-old female was admitted to the emergency room of the Affiliated Hospital of Guizhou Medical University on 28 September 2017, with chief complaint of pain in the right upper abdomen. Ultrasonography of the abdomen showed that the upper segment of the common bile duct was slightly dilated with parallel tubular structures, indicative of biliary ascariasis. Endoscopic retrograde cholangiopancreatography was performed under general anesthesia on 29 September 2017, and an adult Ascaris lumbricoides worm was observed. After the worm was removed from the bile duct, the patient's pain immediately subsided. The patient was successfully cured, without any complications. CONCLUSION: This report emphasizes the need for physicians to consider biliary ascariasis as a possible cause when treating cases of biliary colic.

Near-infrared light-triggered platelet arsenal for combined photothermal-immunotherapy against cancer.

To address long-standing issues with tumor penetration and targeting among cancer therapeutics, we developed an anticancer platelet-based biomimetic formulation (N+R@PLTs), integrating photothermal nanoparticles (N) and immunostimulator (R) into platelets (PLTs). Exploiting the aggregative properties of platelets and high photothermal capacity, N+R@PLTs functioned as an arsenal by targeting defective tumor vascular endothelial cells, accumulating in a positive feedback aggregation cascade at sites of acute vascular damage induced by N-generated local hyperthermia, and subsequently secreting nanosized proplatelets (nPLTs) to transport active components to deep tumor tissue. The immunostimulator augmented the immunogenicity of antigens released from ablated tumors, inducing a stronger immunological response to attack residual, metastatic, and recurrent tumors. Following activation by low-power near-infrared light irradiation, the photothermal and immunological components synergistically provide exceptionally high therapeutic efficacy across nine murine models that mimicked a range of clinical requirements, and, most notably, a sophisticated model based on humanized mouse and patient-derived tumor xenograft.

Engineering Magnetosomes for High-Performance Cancer Vaccination.

A novel cancer vaccine is developed by using Fe3O4 magnetic nanoclusters (MNCs) as the core and cancer cell membranes decorated with anti-CD205 as the cloak. Because of the superparamagnetism and magnetization of MNCs, it is first achieved for the magnetic retention of vaccine in the lymph nodes with a magnetic resonance imaging (MRI) guide, which opened the time window for antigen uptake by dendritic cells (DCs). Meanwhile, the camouflaged cancer cell membranes serve as a reservoir of various antigens, enabling subsequent multiantigenic response. Additionally, the decorated anti-CD205 direct more vaccine into CD8+ DCs, facilitating the major histocompatibility complex (MHC) I cross-presentation. These unique advantages together lead to a great proliferation of T cells with superior clonal diversity and cytotoxic activity. As a result, potent prophylactic and therapeutic effects with few abnormalities are observed on five different tumor models. Therefore, such a cancer-derived magnetosome with the integration of various recent nanotechnologies successfully demonstrates its promise for safe and high-performance cancer vaccination.

Engineering Magnetosomes for Ferroptosis/Immunomodulation Synergism in Cancer.

As traditional anticancer treatments fail to significantly improve the prognoses, exploration of therapeutic modalities is urgently needed. Herein, a biomimetic magnetosome is constructed to favor the ferroptosis/immunomodulation synergism in cancer. This magnetosome is composed of an Fe3O4 magnetic nanocluster (NC) as the core and pre-engineered leukocyte membranes as the cloak, wherein TGF-ß inhibitor (Ti) can be loaded inside the membrane and PD-1 antibody (Pa) can be anchored on the membrane surface. After intravenous injection, the membrane camouflage results in long circulation, and the NC core with magnetization and superparamagnetism enables magnetic targeting with magnetic resonance imaging (MRI) guidance. Once inside the tumor, Pa and Ti cooperate to create an immunogenic microenvironment, which increases the amount of H2O2 in polarized M1 macrophages and thus promotes the Fenton reaction with Fe ions released from NCs. The generated hydroxyl radicals (•OH) subsequently induce lethal ferroptosis to tumor cells, and the exposed tumor antigen, in turn, improves the microenvironment immunogenicity. The synergism of immunomodulation and ferroptosis in such a cyclical manner therefore leads to potent therapeutic effects with few abnormalities, which supports the engineered magnetosomes as a promising combination modality for anticancer therapy.

A single-chromophore-based agent enables rapid sensing of intracellular hypochlorous acid and in-situ photodynamic therapy to cancer cells.

A single-chromophore-based photoactive agent (MB-DOPA) capable of rapid sensing of nanomolar hypochlorous acid (HOCl) and in-situ generating photocytotoxicity to cancer cells was developed using dopamine moiety as the recognition unit and methylene blue (MB) moiety as the fluorescence signaling unit. Specifically, HOCl triggered conversion of the nonfluorescent MB-DOPA to MB enabling far-red fluorescence emission (λmax ∼ 683 nm) and additional ability to photogenerate 1O2 species. Owing to the catechol nature of dopamine characterized with strong electron-donating property, MB-DOPA underwent HOCl-mediated conversion with response time of ∼20 s and a strong fluorescence OFF-to-ON contrast by a factor of more than 3000. The preliminary bioimaging results confirmed the intracellular HOCl sensing ability of MB-DOPA and the in-situ photodynamic therapy (PDT) effectiveness for inducing massive apoptosis of cancer cells. The figure of merits of MB-DOPA, including ability for sensing of nanomolar HOCl with high specificity, rapid response, practicality for intracellular fluorescence imaging, and the in-situ generation of 1O2 for killing tumor cells, is expected to enable diagnosis of early-stage oncogenesis based on the highly specific detection of abnormal HOCl levels in the transformed cells and the simultaneous treatment in biomedical applications.

Nanolongan with Multiple On-Demand Conversions for Ferroptosis-Apoptosis Combined Anticancer Therapy.

As a type of programmed cell death, ferroptosis is distinct from apoptosis. The combination of the two thus provides a promising modality with which to significantly improve anticancer treatment efficacy. To fully utilize this combination, we herein designed a nanolongan delivery system, which possessed a typical structure of one core (up-conversion nanoparticles, UCNP) in one gel particle (Fe3+ cross-linked oxidized starch) with multiple on-demand conversions. The charge conversion of the nanolongan surface in a slightly acidic microenvironment enhanced circulation time for utilizing the enhanced permeability and retention effect, enabled efficient uptake by tumor cells, and induced subsequently lysosomal escape. As the core component, the UCNP with light conversion from near-infrared light to ultraviolet light circumvented the impediment of limited penetration depth and enabled the reduction of Fe3+ to Fe2+. Accordingly, gel networks of nanolongan could be deconstructed due to this valence conversion, leading to the rapid release of Fe2+ and doxorubicin (Dox). In this case, the Fenton reaction between Fe2+ and intracellular H2O2 generated potent reactive oxygen species for ferroptosis, while the co-released Dox penetrated into nucleus and induced apoptosis in a synergistic way. As a result, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that our nanolongan could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

A Turn-On Fluorescent Probe for Detection of Sub-ppm Levels of a Sulfur Mustard Simulant with High Selectivity.

A new type of fluorescent probe capable of detecting a sulfur mustard (SM) simultant at a concentration of 1.2 µM in solution and 0.5 ppm in the gas phase has been developed. Owing to its molecular structure with a thiocarbonyl component and two piperidyl moieties integrated into the xanthene molecular skeleton, this probe underwent a highly selective nucleophilic reaction with the SM simultant and generated a thiopyronin derivative emitting intensive pink fluorescence. The distinct difference in electronic structure between the probe and thiopyronin derivative generated a marked shift of the absorption band from 445 to 567 nm, which enabled an optimal wavelength propitious for exciting the thiopyronin derivative but adverse to the probe. Such efficient separation of the excitation wavelength and tremendous increase in fluorescence quantum yield, from less than 0.002 to 0.53, upon conversion from the probe to the thiopyronin derivative, jointly led to a distinct contrast in the beaconing fluorescence signal (up to 850-fold) and therefore the unprecedented sensitivity for detecting SM species.

Cancer Cell Membrane-Biomimetic Nanoprobes with Two-Photon Excitation and Near-Infrared Emission for Intravital Tumor Fluorescence Imaging.

Biomimetic fluorescent nanoprobes capable of emitting near-infrared (NIR) fluorescence (λmax ≈ 720 nm) upon excitation of 800 nm light were developed. The key conjugated polymer enabled two-photon absorption and Förster resonance energy transfer (FRET) processes within the nanoprobes, which imparted the nanoprobes with ideal NIR-incoming-NIR-outgoing fluorescence features. The cancer cell membrane (CM) coating endowed these nanoprobes with perfect biocompatibility and highly specific targeting ability to homologous tumors. It was believed that CM encapsulation provided an additional protecting layer for the photoactive components residing in the core of nanoprobes for retaining their intrinsic fluorescing ability in the physiological milieu. The long-term structural integrity, excellent photostability (fluorescence decrease <10% upon 30 min illumination of 800 nm pulse laser), high NIR fluorescence quantum yield (∼20%), and long in vivo circulation time of the target nanoprobes were also confirmed. The ability of these feature-packed nanoprobes for circumventing the challenges of absorption and light scattering caused by cellular structures and tissues was definitely confirmed via in vivo and in vitro experiments. The superior performances of these nanoprobes in terms of fluorescence signaling as well as targeting specificity were verified in intravital fluorescence imaging on tumor-bearing model mice. Specifically, these nanoprobes unequivocally enabled high-resolution visualization of the fine heterogeneous architectures of intravital tumor tissue, which proclaims the great potential of this type of probe for high-contrast fluorescence detection of thick biological samples in practical applications.

Beyond a Carrier: Graphene Quantum Dots as a Probe for Programmatically Monitoring Anti-Cancer Drug Delivery, Release, and Response.

On the basis of the unique physicochemical properties of graphene quantum dots (GQDs), we developed a novel type of theranostic agent by loading anticancer drug doxorubicin (DOX) to GQD's surface and conjugating Cy5.5 (Cy) dye to GQD though a cathepsin D-responsive (P) peptide. Such type of agents demonstrated superior therapeutic performance both in vitro and in vivo because of the improved tissue penetration and cellular uptake. More importantly, they are capable of functioning as probes for programmed tracking the delivery and release of anticancer drug as well as drug-induced cancer cell apoptosis through GQD's, DOX's, and Cy's charateristic fluorescence, respectively.

A Colorimetric Fluorescent Probe for SO2 Derivatives-Bisulfite and Sulfite at Nanomolar Level.

A colorimetric fluorescent probe with fluorescence emission feature sensitive to SO2 derivatives, i.e. bisulfite (HSO3-) and sulfite (SO32-), was developed based on the HSO3-/SO32--mediated nucleophilic addition reaction of the probe that. This probe exhibited SO32- sensing ability with detection limit down to 46 nM and desired selectivity over other reference anions and redox species. The preliminary fluorescence bioimaging experiments have validated the practicability of the as-prepared probe for SO2 derivatives sensing in living cells.

A BODIPY-Based Fluorescent Probe for Detection of Subnanomolar Phosgene with Rapid Response and High Selectivity.

A new type of phosgene probe with a limit of detection down to 0.12 nM, response time of less than 1.5 s, and high selectivity over other similarly reactive toxic chemicals was developed using ethylenediamine as the recognition moiety and 8-substituted BODIPY unit as the fluorescence signaling component. The probe undergoes sequential phosgene-mediated nucleophilic substitution reaction and intramolecular cyclization reaction with high rate, yielding a product with the intramolecular charge transfer (ICT) process from amine to the BODIPY core significantly inhibited. Owing to the emission feature of 8-substituted BODIPY that is highly sensitive to the substituent's electronic nature, such inhibition on the ICT process strikingly generates strong fluorescence contrast by a factor of more than 23 300, and therefore creates the superhigh sensitivity of the probe for phosgene. Owing to the high reactivity of ethylenediamine of the probe in nucleophilic substitution reactions, the probe displays a very fast response rate to phosgene.

Photoswitching Near-Infrared Fluorescence from Polymer Nanoparticles Catapults Signals over the Region of Noises and Interferences for Enhanced Sensitivity.

As a very sensitive technique, photoswitchable fluorescence not only gains ultrasensitivity but also imparts many novel and unexpected applications. Applications of near-infrared (NIR) fluorescence have demonstrated low background noises, high tissue-penetrating ability, and an ability to reduce photodamage to live cells. Because of these desired features, NIR-fluorescent dyes have been the premium among fluorescent dyes, and probes with photoswitchable NIR fluorescence are even more desirable for enhanced signal quality in the emerging optical imaging modalities but rarely used because they are extremely challenging to design and construct. Using a spiropyran derivative functioning as both a photoswitch and a fluorophore to launch its periodically modulated red fluorescence excitation energy into a NIR acceptor, we fabricated core-shell polymer nanoparticles exhibiting a photoswitchable fluorescence signal within the biological window (∼700-1000 nm) with a peak maximum of 776 nm. Live cells constantly synthesize new molecules, including fluorescent molecules, and also endocytose exogenous particles, including fluorescent particles. Upon excitation at different wavelengths, these fluorescent species bring about background noises and interferences covering nearly the whole visible region and therefore render many intracellular targets unaddressable. The oscillating NIR fluorescence signal with an on/off ratio of up to 67 that the polymer nanoparticles display is beyond the typical background noises and interferences, thus producing superior sharpness, reliability, and signal-to-noise ratios in cellular imaging. Taking these salient features, we anticipate that these types of nanoparticles will be useful for in vivo imaging of biological tissue and other complex specimens, where two-photon activation and excitation are used in combination with NIR-fluorescence photoswitching.

A flavone-based turn-on fluorescent probe for intracellular cysteine/homocysteine sensing with high selectivity.

A new type of flavone-based fluorescent probe (DMAF) capable of cysteine (Cys)/homocysteine (Hcy) sensing with high selectivity over other amino acids was developed. Such type of probe undergoes Cys/Hcy-mediated cyclization reaction with the involvement of its aldehyde group, which suppresses of the photoinduced electron transfer (PET) process of the probe molecule and consequently leads to the enhancement of fluorescence emission upon excitation using visible light. The formation of product of the Cys/Hcy-mediated cyclization reaction was confirmed and the preliminary fluorescence imaging experiments revealed the biocompatibility of the as-prepared probe and validated its practicability for intracellular Cys/Hcy sensing.

Conjugated Polymer-Based Hybrid Nanoparticles with Two-Photon Excitation and Near-Infrared Emission Features for Fluorescence Bioimaging within the Biological Window.

Hybrid fluorescent nanoparticles (NPs) capable of fluorescing near-infrared (NIR) light (centered ∼730 nm) upon excitation of 800 nm laser light were constructed. A new type of conjugated polymer with two-photon excited fluorescence (TPEF) feature, P-F8-DPSB, was used as the NIR-light harvesting component and the energy donor while a NIR fluorescent dye, DPA-PR-PDI, was used as the energy acceptor and the NIR-light emitting component for the construction of the fluorescent NPs. The hybrid NPs possess δ value up to 2.3 × 10(6) GM per particle upon excitation of 800 nm pulse laser. The excellent two-photon absorption (TPA) property of the conjugated polymer component, together with its high fluorescence quantum yield (ϕ) up to 45% and the efficient energy transfer from the conjugated polymer to NIR-emitting fluorophore with efficiency up to 90%, imparted the hybrid NPs with TPEF-based NIR-input-NIR-output fluorescence imaging ability with penetration depth up to 1200 µm. The practicability of the hybrid NPs for fluorescence imaging in Hela cells was validated.

Erythrocyte membrane-coated NIR-triggered biomimetic nanovectors with programmed delivery for photodynamic therapy of cancer.

A new type of photodynamic therapy (PDT) agents using upconversion nanoparticles (UCNPs) with incorporated photosensitizers as the inner core and an erythrocyte membrane (RM) decorated with dual targeting moieties as the cloak is developed. Owing to the endogenous nature of RM, the RM-coating endows the PDT agents with perfect biocompatibility and stealth ability to escape from the entrapment by the reticulo-endothelial system (RES). More importantly, owing to the unique nature of erythrocyte as an oxygen carrier in the blood, the RM outer layer of the agents unequivocally facilitates the permeation of ground-state molecular oxygen ((3)O2) and the singlet oxygen ((1)O2) as compared to the previously developed PDT agents with other types of coating. Another salient feature of the as-prepared PDT platform is the decoration of RM with dual targeting moieties for selective recognition of cancer cells and mitochondrial targeting, respectively. The synergistic effect of RM coating and dual-targeting of such feature-packed agents are investigated in tumor-bearing mice and the improved PDT therapeutic efficacy is confirmed, which is the first paradigm where RM-coated NIR-triggered nanovectors with programmed delivery ability is applied in PDT of tumor in vivo.

Dual-functional probes for sequential thiol and redox homeostasis sensing in live cells.

A new type of resorufin-based dual-functional fluorescent probe whose fluorescence emission features are sensitive to thiol compounds and redox homeostasis was developed. Thiols-triggered nucleophilic substitution of the probes converts the nonfluorescent probe to the highly fluorescent resorufin moiety; the released resorufin not only enables fluorescence signaling specific for thiol compounds but functions as a redox indicator with sensitive colorimetric and fluorescence emission change upon redox variation. Preliminary fluorescence imaging experiments have revealed the biocompatibility of the as-prepared probes and validated their practicability for thiol sensing and redox homeostasis mapping in living cells.