Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide-Drug Conjugates.

Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete, single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impacts of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug-alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels as well as their drug release profiles showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials.

Cytoplasmic Ca2+ influx mediates iron- and reactive oxygen species-dependent ferroptotic cell death in rice immunity.

Iron- and reactive oxygen species (ROS)-dependent ferroptosis occurs in plant cells. Ca2+ acts as a conserved key mediator to control plant immune responses. Here, we report a novel role of cytoplasmic Ca2+ influx regulating ferroptotic cell death in rice immunity using pharmacological approaches. High Ca2+ influx triggered iron-dependent ROS accumulation, lipid peroxidation, and subsequent hypersensitive response (HR) cell death in rice (Oryza sativa). During Magnaporthe oryzae infection, 14 different Ca2+ influx regulators altered Ca2+, ROS and Fe2+ accumulation, glutathione reductase (GR) expression, glutathione (GSH) depletion and lipid peroxidation, leading to ferroptotic cell death in rice. High Ca2+ levels inhibited the reduction of glutathione isulphide (GSSG) to GSH in vitro. Ca2+ chelation by ethylene glycol-bis (2-aminoethylether)-N, N, N', N'-tetra-acetic acid (EGTA) suppressed apoplastic Ca2+ influx in rice leaf sheaths during infection. Blocking apoplastic Ca2+ influx into the cytoplasm by Ca2+ chelation effectively suppressed Ca2+-mediated iron-dependent ROS accumulation and ferroptotic cell death. By contrast, acibenzolar-S-methyl (ASM), a plant defense activator, significantly enhanced Ca2+ influx, as well as ROS and iron accumulation to trigger ferroptotic cell death in rice. The cytoplasmic Ca2+ influx through calcium-permeable cation channels, including the putative resistosomes, could mediate iron- and ROS-dependent ferroptotic cell death under reduced GR expression levels in rice immune responses.

Using a biocatalyzed reaction cycle for transient and pH-dependent host-guest supramolecular hydrogels.

The formation of transient structures plays important roles in biological processes, capturing temporary states of matter through influx of energy or biological reaction networks catalyzed by enzymes. These natural transient structures inspire efforts to mimic this elegant mechanism of structural control in synthetic analogues. Specifically, though traditional supramolecular materials are designed on the basis of equilibrium formation, recent efforts have explored out-of-equilibrium control of these materials using both direct and indirect mechanisms; the preponderance of such works has been in the area of low molecular weight gelators. Here, a transient supramolecular hydrogel is realized through cucurbit[7]uril host-guest physical crosslinking under indirect control from a biocatalyzed network that regulates and oscillates pH. The duration of transient hydrogel formation, and resulting mechanical properties, are tunable according to the dose of enzyme, substrate, or pH stimulus. This tunability enables control over emergent functions, such as the programmable burst release of encapsulated model macromolecular payloads.

Applying fluorescence spectroscopy coupled with Gaussian band fitting to reveal dynamic variation process of humus fractions from riparian soils along an urbanized river.

Humus, an important fraction of soil organic matter, play an environmental role on nutrients, organic and inorganic pollutants in riparian zones of urbanized rivers. In this study, dynamic variation process of humus fractions from riparian soils was revealed along Puhe River. Composite soil samples of four depths were collected from four land-uses, i.e., eco-conservation area (ECA), industrial area (INA), urban/town area (UTA), rural/agricultural area (RAA). Based on synchronous fluorescence spectra coupled with Gaussian band fitting, fulvic/humic acid predominantly contained tyrosine-like (TYLF), tryptophan-like (TRLF), microbial-like (MLF), fulvic-like (FLF) and humic-like (HLF) substances within each soil profile. TRLF, MLF and FLF (89.43-90.30 %) are the representative components in fulvic-acid, while MLF and HLF (52.81-59.97 %) in humic-acid. Phenolic, carboxylic and humified materials were present in both humus. According to 2-dimensitonal correlation spectroscopy and canonical correlation analysis, fulvic/humic acid within the ECA soil profile could be mainly derived from the degradations of terrestrial plant metabolites and residuals. Within the INA, fulvic-acid could be associated with treated/untreated wastewater, which entered the river and flew into the riparian during high flow period; whereas humic-acid could be relative to the terrestrials. Fulvic-acid had the same source as humic-acid in the UTA, which might be concerned with scattered domestic sewage and livestock wastewater, rather than the fluvial water. Furthermore, the source of fulvic/humic acid in the RAA was the crop metabolites and residuals, apart from the livestock wastewater. Noticeably, the variations of humus fractions in the ECA and RAA roughly occurred in 0-60 cm, while approximately in 20-80 cm in the INA and UTA. This proved that humus fractions in the former were referred to the plant/crop residuals, whereas humus fractions in the latter were those the terrestrials and fluvial water. This study could provide a key support for the construction and restoration of the urbanized riparian zone.

GDF11 mitigates high glucose-induced cardiomyocytes apoptosis by inhibiting the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway.

Diabetic cardiomyopathy remains a formidable health challenge with a high mortality rate and no targeted treatments. Growth differentiation factor 11 (GDF11) has shown promising effects on cardiovascular diseases; however, its role and the underlying mechanism in regulating diabetic cardiomyopathy remain unclear. In this study, we developed mouse models of diabetic cardiomyopathy using leptin receptor-deficient (db/db) mice and streptozocin-induced C57BL/6 mice. The diabetic cardiomyopathy model mice exhibited apparent structural damage in cardiac tissues and a significant increase in the expression of apoptosis-related proteins. Notably, we observed a significant decreased expression of GDF11 in the myocardium of mice with diabetic cardiomyopathy. Moreover, GDF11 cardiac-specific knock-in mice (transgenic mice) exhibited improved cardiac function and reduced apoptosis. Moreover, exogenous administration of GDF11 mitigated high glucose-induced cardiomyocyte apoptosis. Mechanistically, we demonstrated that GDF11 alleviated high glucose-induced cardiomyocytes apoptosis by inhibiting the activation of the alkylation repair homolog 5 (ALKBH5)-forkhead box group O3a (FOXO3)-cerebellar degeneration-related protein 1 transcript (CDR1as)/Hippo signaling pathway. Consequently, this novel mechanism effectively counteracted myocardial cell apoptosis, providing valuable insights into potential therapeutic strategies for clinical diabetic cardiomyopathy.

LncRNA CCRR Attenuates Postmyocardial Infarction Inflammatory Response by Inhibiting the TLR Signalling Pathway.

BACKGROUND: Timely and proper suppression of inflammation can effectively reduce myocardial injury and promote the postmyocardial infarction (post-MI) wound-healing process. We have previously found that cardiac conduction regulatory RNA (CCRR), a long noncoding RNA (lncRNA) transcribed by the gene located on chromosome 9, with abundant expression in the heart, elicits antiarrhythmic effects in heart failure, and this is a continuing study on the role of CCRR in MI. METHODS: CCRR was overexpressed in CCRR transgenic mice or after injection of adeno-associated virus-9 (AAV-9). MI surgery was performed, and cardiac function was assessed in vivo by echocardiography, followed by histologic analyses. Western blot analysis and qRT-PCR were performed to investigate the effects of CCRR on macrophages, cardiomyocytes, and cardiomyocytes cocultured with macrophages. Through microarray analysis and RNA-binding protein immunoprecipitation (RIP) and other related techniques were also employed to study the effects of CCRR on Toll-like receptor (TLR)2 and TLR4. RESULTS: We found that CCRR level was significantly decreased with increases in proinflammatory cytokines and activation of the TLR signalling pathway in the heart of the 3-day MI mice. CCRR overexpression downregulated TLR2 and TLR4 in MI and effectively inhibited the inflammatory responses in primary cardiomyocytes and macrophages cultured under hypoxic conditions. Downregulation of CCRR induced excessive inflammatory responses by activating the TLR signalling pathway. CCRR acted by suppressing TLR2 and TLR4 to inhibit the secretion of proinflammatory factors to reduce infarct size, thereby improving cardiac function. CONCLUSIONS: CCRR protected cardiomyocytes against MI injury by suppressing inflammatory response through targeting the TLR signalling pathway.

Insulin-Dendrimer Nanocomplex for Multi-Day Glucose-Responsive Therapy in Mice and Swine.

The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose-directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once-weekly administration, are on the horizon, there is still no approved therapy that offers glucose-responsive insulin function. Herein, a nanoscale complex combining both electrostatic- and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affinity glucose-binding motif yields an injectable insulin depot affording both glucose-directed and long-lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose-responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic- and dynamic-covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose-responsive insulin depot for week-long control following a single routine injection.

Long non-coding RNA LHX1-DT regulates cardiomyocyte differentiation through H2A.Z-mediated LHX1 transcriptional activation.

Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they regulate early stage cardiomyocyte differentiation. In this study, we identified a specific lncRNA called LHX1-DT, which is transcribed from a bidirectional promoter of LIM Homeobox 1 (LHX1) gene. Our findings demonstrated that LHX1-DT is nuclear-localized and transiently elevated expression along with LHX1 during early differentiation of cardiomyocytes. The phenotype was rescued by overexpression of LHX1 into the LHX1-DT-/- hESCs, indicating LHX1 is the downstream of LHX1-DT. Mechanistically, we discovered that LHX1-DT physically interacted with RNA/histone-binding protein PHF6 during mesoderm commitment and efficiently replaced conventional histone H2A with a histone variant H2A.Z at the promoter region of LHX1. In summary, our work uncovers a novel lncRNA, LHX1-DT, which plays a vital role in mediating the exchange of histone variants H2A.Z and H2A at the promoter region of LHX1.

Characterizing dissolved organic matter and bacterial community interactions in a river network under anthropogenic landcover.

Anthropogenic landcover could rise nutrient concentrations and impact the characteristics and bioavailability of dissolved organic matter (DOM) in a river network. Exploring the interactions between DOM and microbials might be conducive to revealing biogeochemistry behaviors of organic matter. In this study, synchronous fluorescence spectra (SFS) with Gaussian band fitting and two-dimensional correlation spectroscopy (2D-COS) were employed to identify DOM fractions and reveal their interactions with bacterial communities. DOM was extracted from a river network under eco-agricultural rural (RUR), eco-residential urban (URB), eco-economical town (TOW), and eco-industrial park (IND) regions in Jiashan Plain of eastern China. The overlapping peaks observed in the SFS were successfully separated into four fractions using Gaussian band fitting, i.e., tyrosine-like fluorescence (TYLF), tryptophan-like fluorescence (TRLF), microbial humic-like fluorescence (MHLF), and fulvic-like fluorescence (FLF) materials. Across all four regions, TRLF (44.79% ± 7.74%) and TYLF (48.09% ± 8.85%) were the dominant components. Based on 2D-COS, variations of TYLF and TRLF were extremely larger than those of FLF in RUR-TOW. However, in URB-IND, the former exhibited lower variations compared to the latter. These suggested that FLF be likely derived continuously from lignin and other residue of terrestrial plant origin along the river network, and TYLF and TRLF be originated discontinuously from domestic wastewater in RUR-TOW. By high-throughput sequenced OTUs, the number of organisms in RUR-TOW could be higher than those in URB-IND, while genes associated with carbohydrate metabolism were lower in former than those in the latter. According to co-occurrence networks, microbes could promote the production of TYLF and TRLF in RUR-TOW. In contrast, microbial communities in URB-IND might contribute to decompose FLF. The obtained results could not only reveal interactions between DOM fractions and bacterial communities in the river network, but this methodology may be applied to other water bodies from different landscapes.

Study of coaxial-dual-gap dielectric barrier discharge based on capillary: discharge characteristics and Escherichia coli decontamination.

AIMS: The medical capillary catheters occupy a high proportion of medical diagnosis, monitoring, and treatment devices, and will cause serious cross-infection without being disinfected adequately. This paper presents a new plasma structure for efficient inactivation of harmful microorganisms in medical capillaries. METHODS AND RESULTS: An innovative coaxial-dual-gap dielectric barrier discharge reactor powered by nanosecond-pulsed power supply was designed for disinfection of Escherichia coli (E. coli) inside and outside medical capillary catheters in this work. Atmospheric helium plasma (AHP) and atmospheric air plasma (AAP) were successfully obtained inside and outside capillary (0.6 mm inner diameter and 1.0 mm outer diameter), respectively. The electrical and optical characteristics of AHP and AAP were investigated. As the threshold of applied voltage amplitude (Uamp) was <7.0 kV, only one helium glow discharge was generated inside the capillary at the rising and falling stages of pulse voltage. As the Uamp exceeded the threshold, two helium glow discharges were generated that further caused generation of air discharge. Under the Uamp of 9.0 kV, the production of AHP lowered the breakdown voltage in air gap, resulting in the formation of high-volume and uniform AAP, which was conducive to the realization of full inactivation. The inactivation rates of E. coli reached 98.13% and 99.99% by 2 min AHP and 0.5 min AAP treatment, respectively. CONCLUSIONS: The electrical stress of AHP and the reactive oxygen and nitrogen species produced by AAP were contributed to the inactivation of E. coli. The results of SEM (Scanning Electron Microscope) show that plasma treatment can destroy the cellular structure of E. coli.

Insight into suppression of dibutyl phthalate on DOM removal during municipal sewage treatment using fluorescence spectroscopy with PARAFAC and moving-window 2D-COS.

Dibutyl phthalate (DBP) has been widely detected in municipal and industrial wastewater, which could indirectly inhibit pollutant removals, especially degradation of dissolved organic matter (DOM). Here, the inhibition of DBP on DOM removal from wastewater in pilot-scale A2O-MBR system was investigated by fluorescence spectroscopy with two-dimensional correlation (2D-COS) and structural equation modeling (SEM). Seven components were extracted from DOM using parallel factor analysis, i.e., tryptophan-like (C1 and C2), fulvic-like (C4), tyrosine-like (C5), microbial humic-like (C6) and heme-like (C7). The tryptophan-like had a blue-shift at DBP occurrence, defined as blue-shift tryptophan-like (C3). DBP with 8 mg L-1 exhibited a stronger inhibition on removals of DOM fractions, extraordinarily tyrosine-like and tryptophan-like in anoxic unit than DBP of 6 mg L-1 by moving-window 2D-COS. The indirect removals of C1 and C2 through the C3 removal were more strongly inhibited by 8 mg L-1 DBP than those by 6 mg L-1 DBP, while the former exhibited a weaker inhibition on the direct degradation of C1 and C2 than the latter via SEM. Based on metabolic pathways, abundances of key enzymes secreted by microorganism in anoxic unit, degrading tyrosine-like and tryptophan-like, were higher in wastewater with 6 mg L-1 DBP than those with 8 mg L-1 DBP. These could provide a potential approach for online monitoring of DBP concentrations in wastewater treatment plants, which could rectify operating parameters, and then enhance the treatment efficiencies.

Explore variations of DOM components in different landcover areas of riparian zone by EEM-PARAFAC and partial least squares structural equation model.

Dissolved organic matter (DOM) plays key roles in species-distribution of contaminants and the biogeochemical cycle of carbon in ecosystems. Riparian zone is the representative of water-land ecotone and controls the DOM exchange between water and land. However, the variance of DOM in different landcover areas of an urban river riparian zone is unknown. In this study, fluorescence excitation-emission matrix (EEM) spectroscopy coupled with parallel factor analysis (PARAFAC) and partial least squares structural equation model (PLS-SEM) was applied to character dissolved organic matter (DOM) fractions in four types of landcover riparian areas (natural forest, artificial forest, semi-natural grassland, and cropland) of Puhe River and trace latent factors. Soil samples were collected at 0-20 cm, 20-40 cm, 40-60 cm, and 60-80 cm. The results showed that soil DOM components and humification varied between forests with grassland and cropland samples, and soil humification was obviously higher in the forest samples than that in the grassland and cropland samples. In the natural and artificial forest soils, the humic/fulvic-like were the dominant fractions of DOM, whose variations were smaller than the protein-like with soil depths. However, the tyrosine-like was the representative component in the grassland and cropland soils, whose variation was smaller than the humus substances. According to the PLS-SEM, the DOM components and humification were affected by soil physiochemical properties and DOM sources. The humification in the forest soils had a positive correlation with tryptophan-like, which derived from blended source of the autochthonous and terrigenous. Nevertheless, a positive correlation was observed between humification and humus substances, which could derive from microbial degradation of tyrosine-like, in the grassland and cropland soils. Moreover, the soil physiochemical properties were negatively related to DOM components in all soil samples, which could affect indirectly soil humification. Therefore, EEM combined with PARAFAC and PLS-SEM might be an effective method to investigate DOM fractions and trace the latent factors in different landcover areas of the riparian zone.

Machine Learning-Assisted Rapid Screening of Four Types of New Psychoactive Substances in Drug Seizures.

Over the past few years, new psychoactive substances (NPS) have become a global health and social problem because of their wide variety, constant structural renewal, vague legal definitions, and rapid adaptation to legal restrictions. The rapid structural modifications of NPS have posed significant challenges for the screening and identification of these new substances using traditional mass spectrometric techniques based on reference substances or a mass spectral database. Here, we propose supervised machine learning (ML) classification models such as k-nearest neighbors, support vector machine, random forest, and multigrained cascade forest for the rapid screening of NPS using mass spectrometric data. This approach utilizes ML methods to learn the statistical probability distributions of mass spectral data for NPS and non-NPS. Four classification ML models were generated and evaluated using a data set comprising 567 LC-MS and 732 GC-MS spectra. Through cross validation, we achieved an F1 score of 0.35-0.97. These algorithms were applied in conjunction with mass spectrometry techniques for the detection of six seizures including electronic cigarette oil and suspected powdered substances netted in drug trafficking cases. The models provided warning signals for synthetic cannabinoids, synthetic cathinones, and fentanyl. Thus, an early warning system was successfully established, which provided a useful method for reliable and effective identifications of unknown NPS.

Transient and Dissipative Host-Guest Hydrogels Regulated by Consumption of a Reactive Chemical Fuel.

The transient self-assembly of molecules under the direction of a consumable fuel source is fundamental to biological processes such as cellular organization and motility. Such biomolecular assemblies exist in an out-of-equilibrium state, requiring continuous consumption of high energy molecules. At the same time, the creation of bioinspired supramolecular hydrogels has traditionally focused on associations occurring at the thermodynamic equilibrium state. Here, hydrogels are prepared from cucurbit[7]uril host-guest supramolecular interactions through transient physical crosslinking driven by the consumption of a reactive chemical fuel. Upon action from this fuel, the affinity and dynamics of CB[7]-guest recognition are altered. In this way, the lifetime of transient hydrogel formation and the dynamic modulus obtained are governed by fuel consumption, rather than being directed by equilibrium complex formation.

Applying synchronous fluorescence spectra with Gaussian band fitting and two-dimensional correlation to characterize structural composition of DOM from soils in an aquatic-terrestrial ecotone.

Dissolved organic matter (DOM), the primary participant of carbon and nitrogen cycle, has a great impact on the behavior and fate of organic pollutants and heavy metals in eutrophic lakes. The dynamic spectral properties of DOM fractions were revealed in an aquatic-terrestrial ecotone under the different types of land use. Composite soil samples of different depths (0-20, 20-40 and 40-60 cm) were collected from four different land uses along a disturbed-impact gradient in Taihu Lake, China, i.e., grassland (GRL), forest land (FOL), paddy field (PAF), and vegetable field (VEF). DOM mainly consisted of tyrosine-like material (TYLF), tryptophan-like material (TRLF), microbial humic-like material (MHLF), fulvic-like material (FLF) and humic-like material (HLF) within all soil profiles, where TRLF was the dominant component (61.30 %) using synchronous fluorescence spectroscopy (SFS) combined with principal component analysis and Gaussian band fitting. Based on two-dimensional correlation spectroscopy with SFS and Fourier transform infrared, the variation order of DOM fractions was FLF → MHLF → HLF → TRLF → TYLF within the GRL soil profile, and MHLF exhibited an oppositive change with aliphatic OH and amide I in protein. The order of DOM fractions was MHLF → FLF → HLF → TYLF → TRLF within the FOL soil profile, and the change trend of MHLF remained oppositive with aliphatic OH and CO in ester. The order of DOM within the PAF soil profile fractions was TRLF → MHLF → HLF → TYLF → FLF, and changing trends of TYLF were oppositive to aliphatic OH, CH bending vibration, CH bending vibration and CO in ester. The order of DOM fractions was HLF → TYLF → TRLF → FLF → MHLF within the VEF soil profile, where the changing trend TYLF remained oppositive to aliphatic OH, CH deformations in lignin and aliphatic group and amide I in protein. This study may provide important support for alleviating lake water eutrophication or pollution.

Rice iron storage protein ferritin 2 (OsFER2) positively regulates ferroptotic cell death and defense responses against Magnaporthe oryzae.

Ferritin is a ubiquitous iron storage protein that regulates iron homeostasis and oxidative stress in plants. Iron plays an important role in ferroptotic cell death response of rice (Oryza sativa) to Magnaporthe oryzae infection. Here, we report that rice ferritin 2, OsFER2, is required for iron- and reactive oxygen species (ROS)-dependent ferroptotic cell death and defense response against the avirulent M. oryzae INA168. The full-length ferritin OsFER2 and its transit peptide were localized to the chloroplast, the most Fe-rich organelle for photosynthesis. This suggests that the transit peptide acts as a signal peptide for the rice ferritin OsFER2 to move into chloroplasts. OsFER2 expression is involved in rice resistance to M. oryzae infection. OsFER2 knock-out in wild-type rice HY did not induce ROS and ferric ion (Fe3+) accumulation, lipid peroxidation and hypersensitive response (HR) cell death, and also downregulated the defense-related genes OsPAL1, OsPR1-b, OsRbohB, OsNADP-ME2-3, OsMEK2 and OsMPK1, and vacuolar membrane transporter OsVIT2 expression. OsFER2 complementation in ΔOsfer2 knock-out mutants restored ROS and iron accumulation and HR cell death phenotypes during infection. The iron chelator deferoxamine, the lipid-ROS scavenger ferrostatin-1, the actin microfilament polymerization inhibitor cytochalasin E and the redox inhibitor diphenyleneiodonium suppressed ROS and iron accumulation and HR cell death in rice leaf sheaths. However, the small-molecule inducer erastin did not trigger iron-dependent ROS accumulation and HR cell death induction in ΔOsfer2 mutants. These combined results suggest that OsFER2 expression positively regulates iron- and ROS-dependent ferroptotic cell death and defense response in rice-M. oryzae interactions.

NAD+ attenuates cardiac injury after myocardial infarction in diabetic mice through regulating alternative splicing of VEGF in macrophages.

Diabetic mellitus (DM) complicated with myocardial infarction (MI) is a serious clinical issue that remained poorly comprehended. The aim of the present study was to investigate the role of NAD+ in attenuating cardiac damage following MI in diabetic mice. The cardiac dysfunction in DM mice with MI was more severe compared with the non-diabetic mice and NAD+ administration could significantly improve the cardiac function in both non-diabetic and diabetic mice after MI for both 7 days and 28 days. Moreover, application of NAD+ could markedly reduce the cardiac injury area of DM complicated MI mice. Notably, the level of NAD+ was robustly decreased in the cardiac tissue of MI mice, which was further reduced in the DM complicated mice and NAD+ administration could significantly restore the NAD+ level. Furthermore, NAD+ was verified to facilitate the angiogenesis in the MI area of both diabetic mice and non-diabetic mice by microfil perfusion assay and immunofluorescence. Additionally, we demonstrated that NAD+ promoted cardiac angiogenesis after myocardial infarction in diabetic mice by promoting the M2 polarization of macrophages. At the molecular level, NAD+ promoted the secretion of VEGF in macrophages and therefore facilitating migration and tube formation of endothelial cells. Mechanistically, NAD+ was found to promote the generation of pro-angionesis VEGF165 and inhibit the generation of anti-angionesis VEGF165b via regulating the alternative splicing factors of VEGF (SRSF1 and SRSF6) in macrophages. The effects of NAD+ were readily reversible on deficiency of it. Collectively, our data showed that NAD+ could attenuate myocardial injury via regulating the alternative splicing of VEGF and promoting angiogenesis in diabetic mice after myocardial infarction. NAD+ administration may therefore be considered a potential new approach for the treatment of diabetic patients with myocardial infarction.

Applying EEM-PARAFAC combined with moving-window 2DCOS and structural equation modeling to characterize binding properties of Cu (II) with DOM from different sources in an urbanized river.

Dissolved organic matter (DOM) in aquatic environment distinctly affects the behavior and fate of heavy metals via complexation, while the interfacial mechanisms and processes are still lacking in detail. Here, Cu (II) binding characteristics of DOM originated from hilly (NDOM), rural (RDOM) and urban (UDOM) regions in an urbanized river was explored by fluorescence excitation-emission matrix spectroscopy (EEM) combined with principal component coefficients, parallel factor analyses (PARAFAC), moving-window two-dimensional correlation spectroscopy (MW2DCOS) and structural equation modeling (SEM). Eight components were extracted from the titrants through EEM-PARAFAC, i.e., phenol-like substance (C1), tyrosine-like substance (C2), visible tryptophan-like substance (C3), ultraviolet tryptophan-like substance (C4), recent biological production (C5), wastewater-derived organic matter (C6), microbial humic-like substance (C7) and fulvic-like substance (C8). Interestingly, NDOM only contained C1, C3, C5 and C8, while nearly all components were found in RDOM (except for C2) and UDOM (except for C4). The f value of C1 (1.239) in NDOM was much higher than those in RDOM (0.134) and UDOM (0.115), so was of C8. It indicated that phenol-like and fulvic-like derived from autochthonous sources exhibited great binding ratios in the complexation with Cu (II). Moreover, C3 and C5 from UDOM exhibited higher f values (0.591 and 1.983) than those from NDOM and RDOM, suggesting that Cu (II) has a great binding capacity on protein-like from domestic and industrial wastewater. The MW2DCOS revealed that phenol-like and protein-like in NDOM and RDOM were essential for the binding of 160 µmol L-1 Cu (II), whereas fulvic-like in NDOM and UDOM could react significantly with 10 µmol L-1 Cu (II). Based on SEM, Cu (II) concentration had a negative direct effect on the fluorescence intensity of C7 or C8, whereas it showed an indirect positive effect on C7 or C8 through influencing C5, so was C6. It suggested that Cu (II) showed an indirect positive effect on the C8. This study might present a further comprehend of the environmental behaviors of Cu (II) in rivers.

LncRNA-ZFAS1 Promotes Myocardial Ischemia-Reperfusion Injury Through DNA Methylation-Mediated Notch1 Down-Regulation in Mice.

The most devastating and catastrophic deterioration of myocardial ischemia-reperfusion injury (MIRI) is cardiomyocyte death. Here we aimed to evaluate the role of lncRNA-ZFAS1 in MIRI and delineate its mechanism of action. The level of lncRNA-ZFAS1 was elevated in MIRI hearts, and artificial knockdown of lncRNA-ZFAS1 in mice improved cardiac function. Notch1 is a potential target of lncRNA-ZFAS1, and lncRNA-ZFAS1 could bind to the promoter region of Notch1 and recruit DNMT3b to induce Notch1 methylation. Nicotinamide mononucleotide could promote the expression of Notch1 by competitively inhibiting the expression of DNMT3b and improving the apoptosis of cardiomyocytes and cardiac function.

An Automatic Identification Method of Crested Ibis (Nipponia nippon) Habitat Based on Spatiotemporal Density Detection.

To address the current challenges of the heavy workload, time-consuming nature and labor-intensiveness involved in existing crested ibis's (Nipponia nipponTemminck, 1835) habitat identification approaches, this paper proposes an automatic habitat identification method based on spatiotemporal density detection. With consideration of the characteristics of the crested ibis's trajectory data, such as aggregation, repeatability, and uncertainty, this method achieves detecting the crested ibis's stopping points by using the spatial characteristics of the trajectory data. On this basis, an improved spatiotemporal clustering-based DBSCAN method is proposed in this paper, incorporating temporal characteristics of the trajectory data. By combining the spatial and temporal features, the proposed method is able to accurately identify the roosting and foraging sites among the crested ibis's stopping points. Supported by remote sensing images and field investigations, it was found that the method proposed in this paper has a good clustering effect and can effectively identify the crested ibis's foraging sites and overnight roosting areas. Specifically, the woodland, farmland, and river areas are the common foraging sites for the crested ibis, while the woodland with large trees is their common overnight site. Therefore, the method proposed in this paper can provide technical support for identifying and protecting the crested ibis's habitats.