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.

Advancing fluorescence tracing with 3D-2D spectral conversion: A mixed culture on microbial degradation mechanisms of DOM from a large-scale watershed.

Fluorescence tracing, known for its precision, rapid application, and cost-effectiveness, faces challenges due to the microbial degradation of dissolved organic matter (DOM) in aquatic environments, altering its original spectral fingerprint. This study conducted a 15-day microcosm experiment to examine the effects of biodegradation on the spectral properties of DOM from various sources: livestock excrement (EXC), urban sewage (URB), industrial wastewater (IND), and riparian topsoil (tDOM). Our findings show that while the spectral structures of DOM from different sources change during 15 days of microbial degradation, these changes do not overlap or interfere with each other. However, distinguishing between tDOM and URB in the presence of both IND and EXC is only possible at high resolution. Spectral index calculations revealed significant fluctuations and interference in FI and BIX indices among samples from different sources due to microbial degradation. In contrast, the HIX index exhibited independent fluctuations and remained a reliable spectral index for tracing. LEfSe (Linear discriminant analysis Effect Size) identified characteristic bio-indicators (CBI) for each DOM source. The CBI for tDOM and URB differed significantly; tDOM showed a marked CBI only within the first four days of microbial degradation, with a sharp decline in abundance thereafter, while URB's CBI remained abundant for 12 days. Similarly, IND's CBI maintained high relative abundance for the first 12 days. EXC's CBI was unique, showing a distinct and stable community only after six days of degradation, likely due to its high bioavailability and initial rapid microbial utilization. This study addresses the temporal variability in spectral tracing techniques caused by pollutant biodegradation. We developed a combined spectral-biological tracing technique using the "three-dimensional to two-dimensional" method along with bio-indicators, enhancing the accuracy and timeliness of spectral tracing.

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.

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.

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.

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.

Inactivation of E. coli, S. aureus, and Bacteriophages in Biofilms by Humidified Air Plasma.

In this study, humidified air dielectric barrier discharge (DBD) plasma was used to inactivate Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and bacteriophages in biofilms containing DNA, NaCl, carbohydrates, and proteins. The humidified DBD plasma was very effective in the inactivation of microbes in the (≤1.0 µm) biofilms. The number of surviving E. coli, S. aureus, and bacteriophages in the biofilms was strongly dependent on the constituent and thickness of the biofilms and was greatly reduced when the plasma treatment time increased from 5 s to 150 s. Our analysis shows that the UV irradiation was not responsible for the inactivation of microbes in biofilms. The short-lived RONS generated in the humidified air DBD plasma were not directly involved in the inactivation process; however, they recombined or reacted with other species to generate the long-lived RONS. Long-lived RONS diffused into the biofilms to generate very active species, such as ONOOH and OH. This study indicates that the geminated NO2 and OH pair formed due to the homolysis of ONOOH can cause the synergistic oxidation of various organic molecules in the aqueous solution. Proteins in the biofilm were highly resistant to the inactivation of microbes in biofilms, which is presumably due to the existence of the unstable functional groups in the proteins. The unsaturated fatty acids, cysteine-rich proteins, and sulfur-methyl thioether groups in the proteins were easily oxidized by the geminated NO2 and OH pair.

Supramolecular Hydrogels via Light-Responsive Homoternary Cross-Links.

Host-guest physical cross-linking has been used to prepare supramolecular hydrogels for various biomedical applications. More recent efforts to endow these materials with stimuli-responsivity offers an opportunity to precisely tune their function for a target use. In the context of light-responsive materials, azobenzenes are one prevailing motif. Here, an asymmetric azobenzene was explored for its ability to form homoternary complexes with the cucurbit[8]uril macrocycle, exhibiting an affinity (Keq) of 6.21 × 1010 M-2 for sequential binding, though having negative cooperativity. Copolymers were first prepared from different and tunable ratios of NIPAM and DMAEA, and DMAEA groups were then postsynthetically modified with this asymmetric azobenzene. Upon macrocycle addition, these polymers formed supramolecular hydrogels; relaxation dynamics increased with temperature due to temperature-dependent affinity reduction for the ternary complex. Application of UV light disrupted the supramolecular motif through azobenzene photoisomerization, prompting a gel-to-sol transition in the hydrogel. Excitingly, within several minutes at room temperature, thermal relaxation of azobenzene to its trans state afforded rapid hydrogel recovery. By revealing this supramolecular motif and employing facile means for its attachment onto pre-synthesized polymers, the approach described here may further enable stimuli-directed control of supramolecular hydrogels for a number of applications.

Revealing heavy metal correlations with water quality and tracking its latent factors by canonical correlation analysis and structural equation modeling in Dongjianghu Lake.

Decreasing levels of water quality and elevated concentrations of heavy metals in freshwaters can pose global challenges for drinking water sources. Multivariate statistical techniques have been applied on data matrices of water quality and heavy metals for keen characterization of their spatio-temporal variations, exploration of latent factors, and identification of pollution sources. Non-metric multidimensional scaling (nMDS), canonical correlation analysis (CCA), and structural equation modeling (SEM) were employed to process data matrices of the water quality and heavy metals with 14 parameters measured at 13 sampling sites in Dongjianghu Lake in March, June, August, and December 2016. The sampling sites were grouped into three clusters using the nMDS, suggesting that the increasing order of the water quality levels was approximately midstream < downstream < upstream and lake. The CCA of 14 parameters proved that the Escherichia coli, CODMn, TP, TN, TEMP, DO, and pH were the latent factors to distinguish the sampling sites, suggesting that the natural disturbances further influenced the lake and upstream, while the anthropogenic activities further influenced the midstream and downstream. The CCA of the heavy metals exhibited that the CODMn, F-, and E. coli were the latent factors of the Cu, Zn, and As, while the DO and TEMP were the latent factors of the Cd. This indicated that the Cu, As, and Zn were mainly associated with the anthropogenic activities, while the Cd was predominantly relative to the natural conditions. The SEM of the water quality and heavy metals showed that the weights of CODMn (28.64%), NH3-N (14.96%), BOD5 (14.32%), TN (12.88%), and TP (10.18%) were higher than those of the pH (8.37%), DO (7.73%), TEMP (2.58%), and E. coli (0.34%). This indicated that the former exhibited strong influences on the heavy metals than the latter. Moreover, the CODMn and BOD5 were the key factors of the heavy metals, which should be attributed to the no-point sources, especially the exploitation mining and mill tailings. The water quality assessment by the nMDS, CCA, and SEM can determine the status, trend corresponding to its standards, and trace latent factors and identify possible pollution sources. The study could provide a guide for water quality evaluation and pollution control.

Ultraviolet Photodetector Based on ITO/MgO/ZnO Structure Grown by Hydrothermal Process.

A simple two-step aqueous method was employed to grow MgO nanostructures on ZnO/sapphire at low temperature. The obtained thin MgO nanostructures were uniformly distributed on the surface of ZnO layer and showed the sheet-like structures. Meanwhile, an ultraviolet (UV) photodetector based on ITO/MgO/ZnO structures was fabricated by simple way. The obtained UV detector showed excellent UV sensing properties. This novel method will greatly facilitate fabrication of large-scale metal-insulator-semiconductor with relatively low cost at remarkably low temperature.

[Effects of Effective Fractions of Panax Notoginseng on the Expression of TF and TFPI-2 in Rat En- dometrium with Whole Cycle Exogenous Estrogen Intervention].

Objective To observe the effects of notoginsenoside, Panax notoginseng flavonoids (PNF) , Panax notoginseng acid (PNA) , and their mixtures on the expressions of tissue factor (TF) and tissue factor pathway inhibitor 2 (TFPI-2) in rat endometriaum with whole cycle exogenous estrogen inter- vention. Methods Totally 160 female impuberty rats were randomly divided into the blank group (n =40) and the model group (n =120). Rats in the blank group were administered with normal saline by gastroga- vage for 3 weeks, while those in the model group were administered with estradiol valerate suspension. The two interventions lasted for 3 consecutive weeks. After 3 weeks of intervention, rats with asexual cycle were randomly divided into six groups, i.e., the model group, the continuous estrogen group, the No- toginsenoside group, the PNF group, the PNA group, the mixture group. Rats in the model group, the continuous estrogen group, the Notoginsenoside group, the PNF group, the PNA group, the mixture group were respectively administered with normal saline, estrogen, notoginsenoside, PNF, PNA, and mixture of effective Panax notoginseng fractions by gastrogavage for 2 successive weeks. Expression levels of TF, TFPI-2, TF mRNA, and TFPI-2 mRNA in the endometrium were detected 2 weeks later. Re-sults Compared with the blank group, positive expressions of TF and TF mRNA increased, and positive expressions of TFPI-2 and TFPI-2 mRNA decreased in the model group (P <0. 05, P <0. 01). Compared with the model group, the expressions of TF and TF mRNA significantly increased, the expressions of TF- PI-2 and TFPI-2 mRNA significantly decreased in the estrogen group at the end of the 5th week (P < 0. 01). Compared with the model group and the estrogen group, positive expressions of TF and TF mRNA significantly decreased, positive expressions of TFPI-2 and TFPI-2 mRNA significantly increased in the Notoginsenoside group, the PNF group, the PNA group, the mixture group (P <0. 05, P <0. 01). Com- pared with the Notoginsenoside group, positive expressions of TFPI-2 and TFPI-2 mRNA significantly in- creased in the mixture group (P <0. 05). Compared with the PNF group, the expressions of TF and TF mRNA significantly decreased in the Notoginsenoside group and the mixture group (P <0. 01) ; positive expressions of TFPI-2 increased in the mixture group (P <0. 05, P <0. 01). Conclusions The effective fractions of Panax notoginseng could decrease the-expression of TF and increase the expression of TFPI- 2 in rat endometrium with whole cycle exogenous estrogen intervention. They activated blood circulation and arrested bleeding possibly through inhibiting TF, blocking activation of coagulation system, and re- ducing inflammatory response. Meanwhile, it also could strengthen endometrial extracellular matrix, maintain the endometrial stability, thereby reducing endometrial disintegration and bleeding, and being beneficial for endometrium repairing and remodeling.

Direct observation of magnetic vortex behavior in an ordered La0.7Sr0.3MnO3 dot arrays.

Directly observing the magnetic domain behavior in patterned nanostructures is crucial to the investigation into advanced spin-based devices. Herein, we show that the magnetic vortex behavior can be deterministically observed and controlled in highly spin polarized La0.7Sr0.3MnO3 (LSMO) triangular dots by successive in-field magnetic force microscopy (MFM). Imaging the magnetic domains with MFM shows that most of the LSMO dots exhibit magnetic vortex states with a clockwise or anticlockwise "pinwheel" structure for decreasing the demagnetization energy. Probing the vortex chirality using in-field MFM indicates that the selective spin circulation of the triangular dots depends on the magnetic orientation of the bias nanomagnet with specially designed geometries. Comparison between measurement and simulation reveals that the vortex behavior should be governed by an interface involved pinning strength at the boundaries, as well as a geometrically induced shape anisotropy of the triangular dot, both of which result in shape-dominated magnetic domain reversals.

[Up-regulation of ErbB3-binding protein 1 inhibits the growth of esophageal carcinoma cells].

The objective of this study was to investigate the role of ErbB3-binding protein 1 (Ebp1) in the growth of esophageal squamous cell carcinoma (ESCC) cells and the underlying mechanism. Eca109 and KYSE150 cells were transfected with lentiviral vector carrying Ebp1 gene. The mRNA levels of Ebp1 in esophageal cancer tissues and paired adjacent normal tissues were examined by real-time PCR. The growth and viability of esophageal carcinoma cells were assessed using MTT and crystal violet assays, respectively. Clone-forming abilities of Eca109 and KYSE150 cells were analyzed by soft agar assay. Apoptotic rates of esophageal carcinoma cells were detected by flow cytometry, and expression levels of the proteins involved in apoptosis were assessed by Western blot. Tumorigenicity of Eca109 cells were detected by nude mouse transplantation tumor experiment. The results indicated that the mRNA levels of Ebp1 in esophageal cancer tissues was down-regulated compared with paired adjacent normal tissues. The growth and viability of Eca109 and KYSE150 cells were all suppressed by Ebp1 overexpression. Besides, Ebp1 overexpression induced apoptosis, increased Rb and P53 expressions, and decreased CyclinD1 expression in Eca109 and KYSE150 cells. In addition, Ebp1 overexpression inhibited the tumorigenesis of Eca109 cells in vivo. These results suggest that Ebp1 may suppress the growth of esophageal carcinoma cells in vitro and in vivo by inducing apoptosis.

Inactivation of Escherichia coli Cells in Aqueous Solution by Atmospheric-Pressure N2, He, Air, and O2 Microplasmas.

Atmospheric-pressure N2, He, air, and O2 microplasma arrays have been used to inactivate Escherichia coli cells suspended in aqueous solution. Measurements show that the efficiency of inactivation of E. coli cells is strongly dependent on the feed gases used, the plasma treatment time, and the discharge power. Compared to atmospheric-pressure N2 and He microplasma arrays, air and O2 microplasma arrays may be utilized to more efficiently kill E. coli cells in aqueous solution. The efficiencies of inactivation of E. coli cells in water can be well described by using the chemical reaction rate model, where reactive oxygen species play a crucial role in the inactivation process. Analysis indicates that plasma-generated reactive species can react with E. coli cells in water by direct or indirect interactions.

Electric control of spin in monolayer WSe2 field effect transistors.

We report first-principles theoretical investigations of quantum transport in a monolayer WSe2 field effect transistor (FET). Due to strong spin-orbit interaction (SOI) and the atomic structure of the two-dimensional lattice, monolayer WSe2 has an electronic structure that exhibits Zeeman-like up-down spin texture near the K and K' points of the Brillouin zone. In a FET, the gate electric field induces an extra, externally tunable SOI that re-orients the spins into a Rashba-like texture thereby realizing electric control of the spin. The conductance of FET is modulated by the spin texture, namely by if the spin orientation of the carrier after the gated channel region, matches or miss-matches that of the FET drain electrode. The carrier current I(τ, s) in the FET is labelled by both the valley index and spin index, realizing valleytronics and spintronics in the same device.

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.

Mitogen-Activated Protein Kinase Kinase OsMEK2 Positively Regulates Ca2+ Influx and Ferroptotic Cell Death during Rice Immune Responses.

Mitogen-activated protein (MAP) kinase (MAPK) signaling pathway is important in plant immune responses, involved in iron- and reactive oxygen species (ROS)-dependent ferroptotic cell death mediated by Ca2+. High Ca2+ influx triggered iron-dependent ROS accumulation, lipid peroxidation, and subsequent hypersensitive response (HR) cell death in rice (Oryza sativa). Apoplastic Ca2+ chelation by EGTA during avirulent Magnaporthe oryzae infection altered Ca2+, ROS, and Fe2+ accumulation, increasing rice susceptibility to infection. By contrast, acibenzolar-S-methyl (ASM), a plant defense activator, significantly enhanced Ca2+ influx, and H2O2 accumulation, triggering rice ferroptotic cell death during virulent Magnaporthe oryzae infection. Here, we report a novel role of the MAPK signaling pathway in regulating cytoplasmic Ca2+ increase during ferroptotic cell death in rice immunity, using the ΔOsmek2 knockout mutant rice. The knockout of rice OsMEK2 impaired the ROS accumulation, lipid peroxidation, and iron accumulation during avirulent M. oryzae infection. This study has shown that OsMEK2 could positively regulate iron- and ROS-dependent ferroptotic cell death in rice by modulating the expression of OsNADP-ME, OsRBOHB, OsPLC, and OsCNGC. This modulation indicates a possible mechanism for how OsMEK2 participates in Ca2+ regulation in rice ferroptotic cell death, suggesting its broader role in plant immune responses in response to M. oryzae infection.

Engineering Supramolecular Nanofiber Depots from a Glucagon-Like Peptide-1 Therapeutic.

Diabetes and obesity have emerged as major global health concerns. Glucagon-like peptide-1 (GLP-1), a natural incretin hormone, stimulates insulin production and suppresses glucagon secretion to stabilize and reduce blood glucose levels and control appetite. The therapeutic use of GLP-1 receptor agonists (e.g., semaglutide) has transformed the standard of care in recent years for treating type 2 diabetes and reversing obesity. The native GLP-1 sequence has a very short half-life, and therapeutic advances have come from molecular engineering to alter the pharmacokinetic profile of synthetic GLP-1 receptor agonists to enable once-weekly administration, reduce the frequency of injection, and improve adherence. Efforts to further extend this profile would offer additional convenience or enable entirely different treatment modalities. Here, an injectable GLP-1 receptor agonist depot is engineered through integration of a prosthetic self-assembling peptide motif to enable supramolecular nanofiber formation and hydrogelation. This supramolecular GLP-1 receptor agonistic (PA-GLP1) offers sustained release in vitro for multiple weeks, supporting long-lasting therapy. Moreover, in a rat model of type 2 diabetes, a single injection of the supramolecular PA-GLP1 formulation achieved sustained serum concentrations for at least 40 days, with an overall reduction in blood glucose levels and reduced weight gain, comparing favorably to daily injections of semaglutide. The general and modular approach is also extensible to other next-generation peptide therapies. Accordingly, the formation of supramolecular nanofiber depots offers a more convenient and long-lasting therapeutic option to manage diabetes and treat metabolic disorders.

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.