Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.

Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.

Isoxerophilusins A and B, Two Novel Polycyclic Asymmetric Diterpene Dimers from Isodon xerophilus: Structural Elucidation, Modification, and Inhibitory Activities against α-Glucosidase.

Isoxerophilusins A (1) and B (2), two unprecedented diterpene heterodimers biogenetically from ent-atisanes and abietanes, were isolated from the rhizomes of Isodon xerophilus. Their structures were determined by extensive spectroscopic analysis and single-crystal X-ray diffraction. Selective esterification of 1 generated 11 new derivatives. All derivatives showed excellent α-glucosidase inhibitory activity in comparison to acarbose. Compounds 12 and 13 demonstrated significant inhibition against α-glucosidase with IC50 values of 4.92 and 3.83 µM, respectively.

HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca2+-ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes. HumanIslets.com provides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

An investigation of association between human milk mineral patterns and infant growth.

Introduction: Human milk is widely acknowledged as the optimal food for infant aged 0 ~ 6 months. While there has been extensive documentation on the mineral and trace element composition of human milk, results on the relationship between mineral content and infant growth remain mixed. This cross-sectional study aims to explore human milk mineral patterns and to investigate associations between human milk mineral patterns, human milk metabolomic profile and infant growth. Methods: A total of 200 breast milk samples from seven cities in China was included. Human milk mineral and trace elements was detected by inductively coupled plasma mass spectrometer (ICP-MS). K-means cluster analysis was utilized to derived human milk mineral patterns. Untargeted human milk metabolomic profiles was determined using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Differences of infant growth rate and metabolomic profiles were then compared across patterns identified. Results: Three human milk mineral patterns were identified. Cluster I was characterized as the highest levels of potassium, magnesium and calcium, while the lowest levels of copper, zinc, manganese and selenium. Cluster II showed the most abundant sodium, iron, zinc, manganese and selenium. Cluster III had the lowest levels of sodium, potassium, magnesium, iron and calcium. Infants of cluster I showed significantly higher length-for-age z score (0.60 ± 2.03, p = 0.03). Compared with other clusters, samples of cluster I showed lower expression of metabolites of arachidonic acid (ARA) and nicotinate and nicotinamide metabolism pathway. Discussion: A human milk mineral pattern was identified which is related to increased infant growth rate and altered metabolic signature. Future work is needed to understand these human milk patterns in terms of biologic mechanisms and generalization to other populations.

Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products.

Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.

Amphiphilic Janus Graphene Oxide Acts as a Corrosion Inhibitor to Mitigate the Corrosion Caused by a 1 M HCl Solution on Mild Steel.

Great aqueous dispersibility, a large specific surface area, and high impermeability make graphene oxide (GO) the ideal candidate for a high-performance corrosion inhibitor. Numerous symmetrical modification methods have been reported to enhance the adsorption of GO on metal surfaces in various corrosive media. This work aims to investigate the enhancement and mechanism of unilateral hydrophobic modification on the corrosion inhibition performance of GO. In this study, amphiphilic Janus GO (JGO) was prepared by grafting hydrophobic alkyl chains on one side of GO, and its anticorrosion performance was evaluated via weight loss experiments and electrochemical tests. The results revealed that the corrosion inhibition efficiency for Q235 mild steel (MS) in a 1 M HCl aqueous solution of 25 ppm JGO (81.08%) was much higher than that of GO at the same concentration (22.12%). Furthermore, the Langmuir adsorption isotherm and computational study demonstrated that the synergistic effect of physical adsorption and chemical adsorption promoted the hydrophilic side of JGO close to the surface of the metal, and the dense protective layer was formed by the hydrophobic chains toward the corrosive medium, which effectively hindered the corrosion of MS by the acidic liquid. This study emphasizes the significant role of asymmetrically modified hydrophobic alkyl chains in improving the corrosion prevention performance of GO and provides a perspective for the structural design of GO-based corrosion inhibitors.

Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed -1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element.

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.

Modeling and biological evaluation of pegmolesatide, a novel and potent erythropoiesis-stimulating agent.

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.

In Situ Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System.

Long-acting drug delivery systems are promising platforms to improve patient adherence to medication by delivering drugs over sustained periods and removing the need for patients to comply with oral regimens. This research paper provides a proof-of-concept for the development of a new optimized in situ forming injectable depot based on a tetrabenzylamine-tetraglycine-d-lysine-O-phospho-d-tyrosine peptoid-D-peptide formulation ((NPhe)4GGGGk(AZT)y(p)-OH). The chemical versatility of the peptoid-peptide motif allows low-molecular-weight drugs to be precisely and covalently conjugated. After subcutaneous injection, a hydrogel depot forms from the solubilized peptoid-peptide-drug formulation in response to phosphatase enzymes present within the skin space. This system is able to deliver clinically relevant concentrations of a model drug, the antiretroviral zidovudine (AZT), for 35 days in Sprague-Dawley rats. Oscillatory rheology demonstrated that hydrogel formation began within ∼30 s, an important characteristic of in situ systems for reducing initial drug bursts. Gel formation continued for up to ∼90 min. Small-angle neutron scattering data reveal narrow-radius fibers (∼0.78-1.8 nm) that closely fit formation via a flexible cylinder elliptical model. The inclusion of non-native peptoid monomers and D-variant amino acids confers protease resistance, enabling enhanced biostability to be demonstrated in vitro. Drug release proceeds via hydrolysis of an ester linkage under physiological conditions, releasing the drug in an unmodified form and further reducing the initial drug burst. Subcutaneous administration of (NPhe)4GGGGk(AZT)y(p)-OH to Sprague-Dawley rats resulted in zidovudine blood plasma concentrations within the 90% maximal inhibitory concentration (IC90) range (30-130 ng mL-1) for 35 days.

B3GNT7 regulates mucin O-glycosylation to alleviate colonic inflammation.

BACKGROUND: B3GNT7, a glycosyltransferase of significant importance that is highly expressed in intestinal epithelial cells, plays a pivotal role in intestinal physiological processes. This study elucidates novel insights into the potential role and underlying mechanisms of B3GNT7 in ulcerative colitis (UC). METHODS: An experimental colitis model was induced using DSS in mice to investigate B3GNT7 expression in the colon via transcriptomics and immunohistochemistry. Bioinformatics analysis was employed to delineate the biological functions of B3GNT7. Additionally, the correlation between the transcription levels of B3GNT7 in colonic tissues from patients with UC, sourced from the IBDMDB database, and the severity of colonic inflammation was analyzed to elucidate potential mechanisms. RESULTS: The DSS-induced colitis model was successfully established, and transcriptomic analysis identified a marked downregulation of B3GNT7 expression in the colonic tissues compared to the controls. Functional enrichment analysis indicated B3GNT7's predominant role in mucin O-glycosylation. Protein interaction analysis revealed that B3GNT7 predominantly interacts with members of the mucin MUC family, including MUC2, MUC3, and MUC6. In patients with UC, B3GNT7 transcription levels were significantly reduced, particularly in those with moderate to severe disease activity. The expression level of B3GNT7 exhibited a negative correlation with the endoscopic severity of UC. Gene set enrichment analysis (GSEA) further demonstrated significant enrichment of B3GNT7 in the mucin O-glycosylation synthesis pathway. CONCLUSION: The downregulation of B3GNT7 expression in the colonic tissues of UC patients may contribute to the compromised mucin barrier function and the exacerbation of colitis.

Atomically dispersed low-valent Au boosts photocatalytic hydroxyl radical production.

Providing affordable, safe drinking water and universal sanitation poses a grand societal challenge. Here we developed atomically dispersed Au on potassium-incorporated polymeric carbon nitride material that could simultaneously boost photocatalytic generation of ·OH and H2O2 with an apparent quantum efficiency over 85% at 420 nm. Potassium introduction into the poly(heptazine imide) matrix formed strong K-N bonds and rendered Au with an oxidation number close to 0. Extensive experimental characterization and computational simulations revealed that the low-valent Au altered the materials' band structure to trap highly localized holes produced under photoexcitation. These highly localized holes could boost the 1e- water oxidation reaction to form highly oxidative ·OH and simultaneously dissociate the hydrogen atom in H2O, which greatly promoted the reduction of oxygen to H2O2. The photogenerated ·OH led to an efficiency enhancement for visible-light-response superhydrophilicity. Furthermore, photo-illumination in an onsite fixed-bed reactor could disinfect water at a rate of 66 L H2O m-2 per day.

A Rapid Response System for Elderly Safety Monitoring Using Progressive Hierarchical Action Recognition.

The global trend of population aging presents an urgent challenge in ensuring the safety and well-being of elderly individuals, especially those living alone due to various circumstances. A promising approach to this challenge involves leveraging Human Action Recognition (HAR) by integrating data from multiple sensors. However, the field of HAR has struggled to strike a balance between accuracy and response time. While technological advancements have improved recognition accuracy, complex algorithms often come at the expense of response time. To address this issue, we introduce an innovative asynchronous detection method called Rapid Response Elderly Safety Monitoring (RESAM), which relies on progressive hierarchical action recognition and multi-sensor data fusion. Through initial analysis of inertial sensor data using Kernel Principal Component Analysis (KPCA) and multi-class classifiers, we efficiently reduce processing time and lower the false-negative rate (FNR). The inertial sensor identification serves as a pre-filter, enabling the identification of filtered abnormal signals. Decision-level data fusion is then executed, incorporating skeleton image analysis based on ResNet and the inertial sensor data from the initial step. This integration enables the accurate differentiation between normal and abnormal behaviors. The RESAM method achieves an impressive 97.4% accuracy on the UTD-MHAD database with a minimal delay of 1.22 seconds. On our internally collected database, the RESAM system attains an accuracy of 99%, ranking among the most accurate state-of-the-art methods available. These results underscore the practicality and effectiveness of our approach in meeting the critical demand for swift and precise responses in healthcare scenarios.

Deuteration as a General Strategy to Enhance Azobenzene-Based Photopharmacology.

Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds have been implemented to improve photoswitch characteristics, ranging from the nature of the photoswitch itself (e.g. azobenzenes, dithienylethenes, hemithioindigo) to fine-tuning of aromatic units and substituents. Herein, we present deuterated azobenzene photoswitches as a general means of enhancing the performance of photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity (higher molar extinction coefficient), photoswitch efficiency (higher photoisomerization quantum yield), and photoswitch kinetics (faster macroscopic rate of photoisomerization) with minimal alteration to the underlying structure of the photopharmacological ligand. We report synthesized deuterated azobenzene-based ligands for the optimized optical control of ion channel and G protein-coupled receptor (GPCR) function in live cells, setting the stage for the straightforward, widespread adoption of this approach.

Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels.

The two-pore domain potassium (K2P) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature and phosphorylation. This regulation involves the C-terminus as a polymodal stimulus sensor and the selectivity filter (SF) as channel gate. Using crystallographic up- and down-state structures of TREK-2 as a template for full atomistic molecular dynamics (MD) simulations, we reveal that the SF in down-state undergoes inactivation via conformational changes, while the up-state structure maintains a stable and conductive SF. This suggests an atomistic mechanism for the low channel activity previously assigned to the down state, but not evident from the crystal structure. Furthermore, experimentally by using (de-)phosphorylation mimics and chemically attaching lipid tethers to the proximal C-terminus (pCt), we confirm the hypothesis that moving the pCt towards the membrane induces the up-state. Based on MD simulations, we propose two gating pathways by which movement of the pCt controls the stability (i.e., conductivity) of the filter gate. Together, these findings provide atomistic insights into the SF gating mechanism and the physiological regulation of TREK channels by phosphorylation.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Improvement of biotic nitrate reduction in constructed photoautotrophic biofilm-soil microbial fuel cells.

The biotic nitrate reduction rate in freshwater ecosystems is typically constrained by the scarcity of carbon sources. In this study, 'two-chambers' - 'two-electrodes' photoautotrophic biofilm-soil microbial fuel cells (P-SMFC) was developed to accelerate nitrate reduction by activating in situ electron donors that originated from the soil organic carbon (SOC). The nitrate reduction rate of P-SMFC (0.1341 d-1) improved by âˆ¼ 1.6 times on the 28th day compared to the control photoautotrophic biofilm. The relative abundance of electroactive bacterium increased in the P-SMFC and this bacterium contributed to obtain electrons from SOC. Biochar amendment decreased the resistivity of P-SMFC, increased the electron transferring efficiency, and mitigated anodic acidification, which continuously facilitated the thriving of putative electroactive bacterium and promoted current generation. The results from physiological and ecological tests revealed that the cathodic photoautotrophic biofilm produced more extracellular protein, increased the relative abundance of Lachnospiraceae, Magnetospirillaceae, Pseudomonadaceae, and Sphingomonadaceae, and improved the activity of nitrate reductase and ATPase. Correspondingly, P-SMFC in the presence of biochar achieved the highest reaction rate constant for nitrate reduction (kobs) (0.2092 d-1) which was 2.4 times higher than the control photoautotrophic biofilm. This study provided a new strategy to vitalize in situ carbon sources in paddy soil for nitrate reduction by the construction of P-SMFC.

Ciprofloxacin affects nutrient removal in manganese ore-based constructed wetlands: Adaptive responses of macrophytes and microbes.

Ciprofloxacin (CIP) has received considerable attention in recent decades due to its high ecological risk. However, little is known about the potential response of macrophytes and microbes to varying levels of CIP exposure in constructed wetlands. Therefore, lab-scale manganese ore-based tidal flow constructed wetlands (MO-TFCWs) were operated to evaluate the responses of macrophytes and microbes to CIP over the long term. The results indicated that total nitrogen removal improved from 79.93% to 87.06% as CIP rose from 0 to 4 mg L-1. The chlorophyll content and antioxidant enzyme activities in macrophytes were enhanced under CIP exposure, but plant growth was not inhibited. Importantly, CIP exposure caused a marked evolution of the substrate microbial community, with increased microbial diversity, expanded niche breadth and enhanced cooperation among the top 50 genera, compared to the control (no CIP). Co-occurrence network also indicated that microorganisms may be more inclined to co-operate than compete. The abundance of the keystone bacterium (involved in nitrogen transformation) norank_f__A0839 increased from 0.746% to 3.405%. The null model revealed drift processes (83.33%) dominated the community assembly with no CIP and 4 mg L-1 CIP. Functional predictions indicated that microbial carbon metabolism, electron transfer and ATP metabolism activities were enhanced under prolonged CIP exposure, which may contribute to nitrogen removal. This study provides valuable insights that will help achieve stable nitrogen removal from wastewater containing antibiotic in MO-TFCWs.

Fe-doped Cu-based bimetallic metal-organic frameworks as nanoscale microwave sensitizers for enhancing microwave thermal and dynamic therapy for hepatocellular carcinoma.

Microwave ablation (MWA) is recognized as a novel treatment modality that can kill tumor cells by heating the ions and polar molecules in these cells through high-speed rotation and friction. However, the size and location of the tumor affect the effective ablation range of microwave hyperthermia, resulting in residual tumor tissue and a high recurrence rate. Due to their tunable porous structure and high specific surface area, metal-organic frameworks (MOFs) can serve as microwave sensitizers, promoting microwave energy conversion owing to ion collisions in the porous structure of the MOFs. Moreover, iron-based compounds are known to possess peroxidase-like catalytic activity. Therefore, Fe-doped Cu bimetallic MOFs (FCMs) were prepared through a hydrothermal process. These FCM nanoparticles not only increased the efficiency of microwave-thermal energy conversion as microwave sensitizers but also promoted the generation of reactive oxygen species (ROS) by consuming glutathione (GSH) and promoted the Fenton reaction to enhance microwave dynamic therapy (MDT). The in vitro and in vivo results showed that the combination of MWA and MDT treatment effectively destroyed tumor tissues via microwave irradiation without inducing significant side effects on normal tissues. This study provides a new approach for the combined application of MOFs and microwave ablation, demonstrating excellent potential for future applications.

A comprehensive review on the heterotrophic production of bioactive compounds by microalgae.

Bioactive compounds derived from microalgae have garnered considerable attention as valuable resources for drugs, functional foods, and cosmetics. Among these compounds, photosynthetic pigments and polyunsaturated fatty acids (PUFAs) have gained increasing interest due to their numerous beneficial properties, including anti-oxidant, anti-viral, anti-bacterial, anti-fungal, anti-inflammatory, and anti-tumor effects. Several microalgae species have been identified as rich sources of bioactive compounds, including the Chlorophyceae Dunaliella and Haematococcus, the Bacillariophyta Phaeodactylum and Nitzschia, and the dinoflagellate Crypthecodinium cohnii. However, most of the reported microalgae species primarily grow through autotrophic mechanisms, resulting in low yields and high production costs of bioactive compounds. Consequently, the utilization of heterotrophic microalgae, such as Chromochloris zofingiensis and Nitzschia laevis, has shown significant advantages in the production of astaxanthin and eicosapentaenoic acid (EPA), respectively. These heterotrophic microalgae exhibit superior capabilities in synthesizing target compounds. This comprehensive review provides a thorough examination of the heterotrophic production of bioactive compounds by microalgae. It covers key aspects, including the metabolic pathways involved, the impact of cultivation conditions, and the practical applications of these compounds. The review discusses how heterotrophic cultivation strategies can be optimized to enhance bioactive compound yields, shedding light on the potential of microalgae as a valuable resource for high-value product development.

Genome-wide association study and genomic selection of spike-related traits in bread wheat.

KEY MESSAGE: Identification of 337 stable MTAs for wheat spike-related traits improved model accuracy, and favorable alleles of MTA259 and MTA64 increased grain weight and yield per plant. Wheat (Triticum aestivum L.) is one of the three primary global, staple crops. Improving spike-related traits in wheat is crucial for optimizing spike and plant morphology, ultimately leading to increased grain yield. Here, we performed a genome-wide association study using a dataset of 24,889 high-quality unique single-nucleotide polymorphisms (SNPs) and phenotypic data from 314 wheat accessions across eight diverse environments. In total, 337 stable and significant marker-trait associations (MTAs) related to spike-related traits were identified. MTA259 and MTA64 were consistently detected in seven and six environments, respectively. The presence of favorable alleles associated with MTA259 and MTA64 significantly reduced wheat spike exsertion length and spike length, while enhancing thousand kernel weight and yield per plant. Combined gene expression and network analyses identified TraesCS6D03G0692300 and TraesCS6D03G0692700 as candidate genes for MTA259 and TraesCS2D03G0111700 and TraesCS2D03G0112500 for MTA64. The identified MTAs significantly improved the prediction accuracy of each model compared with using all the SNPs, and the random forest model was optimal for genome selection. Additionally, the eight stable and major MTAs, including MTA259, MTA64, MTA66, MTA94, MTA110, MTA165, MTA180, and MTA164, were converted into cost-effective and efficient detection markers. This study provided valuable genetic resources and reliable molecular markers for wheat breeding programs.