Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy.

ABSTRACT: Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI-therapy failure in people with chronic-phase CML.

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Optically Readable, Physically Unclonable Subwavelength Pixel via Multicolor Quantum Dot Printing for Anticounterfeiting.

We present a secure and user-friendly ultraminiaturized anticounterfeiting labeling technique─the color-encoded physical unclonable nanotag. These nanotags consist of subwavelength spots formed by random combinations of multicolor quantum dots, which are fabricated using a cost-efficient printing method developed in this study. The nanotags support over 170,000 different colors and are inherently resistant to cloning. Moreover, their high brightness and color purity, owing to the quantum dots, ensure an ease of readability. Additionally, these nanotags can function as color-encrypted pixels, enabling the incorporation of labels (such as QR codes) into ultrasmall physically unclonable hidden tags with a resolution exceeding 100,000 DPI. The unique blend of compactness, flexibility, and security positions the color-encoded nanotag as a potent and versatile solution for next-generation anticounterfeiting applications.

Panorama of artery endothelial cell dysfunction in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterized by progressive pulmonary vascular remodeling. The initial cause of pulmonary vascular remodeling is the dysfunction of pulmonary arterial endothelial cells (PAECs), manifested by changes in the categorization of cell subtypes, endothelial programmed cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, et al., overproliferation, senescence, metabolic reprogramming, endothelial-to-mesenchymal transition, mechanosensitivity, and regulation ability of peripheral cells. Therefore, it is essential to explore the mechanism of endothelial dysfunction in the context of PAH. This review aims to provide a comprehensive understanding of the molecular mechanisms underlying endothelial dysfunction in PAH. We highlight the developmental process of PAECs and changes in PAH and summarise the latest classification of endothelial dysfunction. Our review could offer valuable insights into potential novel EC-specific targets for preventing and treating PAH.

Natural and synthetic 5-(3'-indolyl)oxazoles: Biological activity, chemical synthesis and advanced molecules.

5-(3'-Indolyl)oxazole moiety is a privileged heterocyclic scaffold, embedded in many biologically interesting natural products and potential therapeutic agents. Compounds containing this scaffold, whether from natural sources or synthesized, have demonstrated a wide array of biological activities. This has piqued the interest of synthetic chemists, leading to a large number of reported synthetic approaches to 5-(3'-indolyl)oxazole scaffold in recent years. In this review, we comprehensively overviewed the different biological activities and chemical synthetic methods for the 5-(3'-indolyl)oxazole scaffold reported in the literatures from 1963 to 2024. The focus of this study is to highlight the significance of 5-(3'-indolyl)oxazole derivatives as the lead compounds for the lead discovery of anticancer, pesticidal, antimicrobial, antiviral, antioxidant and anti-inflammatory agents, to summarize the synthetic methods for the 5-(3'-indolyl)oxazole scaffold. In addition, the reported mechanism of action of 5-(3'-indolyl)oxazoles and advanced molecules studied in animal models are also reviewed. Furthermore, this review offers perspectives on how 5-(3'-indolyl)oxazole scaffold as a privileged structure might be exploited in the future.

Wireless Gold/Boron-Nitrogen-Codoped Graphene-Based Antenna Immunosensor for the Rapid Detection of Neuron-Specific Enolase.

Tumor-marker immunosensors for rapid on-site detection have not yet been developed because of immunoreaction bottlenecks, such as shortening the reaction time and facilitating incubation. In this study, a gold-boron-nitrogen-codoped graphene (Au-BNG)-based immunosensor antenna was constructed for the rapid detection of neuron-specific enolase (NSE). A Au-BNG radiation electrode with dual functions of antibody protein fixation and signal transmission was developed for the first time. A radiation sample cell was constructed by embedding a radiation electrode into the groove of a poly(dimethylsiloxane) dielectric substrate. The constructed sense antenna achieves accurate detection of NSE with a range from 50 fg mL-1 to 40,000 pg mL-1 and a limit of detection of 10.99 fg mL-1, demonstrating excellent selectivity, stability, and reliability. The tumor-marker detection meter can provide NSE detection results as rapidly as within 2 min by using the new strategy of the microwave self-incubation of tumor markers. This antenna immunosensor is suitable for rapid detection in outpatient clinics and can be developed into household tumor-marker detectors, which would be significant in the early detection, long-term monitoring, and efficacy evaluation of tumors.

Active Assembly of CsPbBr3 Nanorods into Microcolumns by Electric Field in Nonpolar Solvent.

High-precision, controllable, mass-producible assembly of nanoparticles into complex structures or devices holds immense importance in the application across various fields but it remains challenging. Here a highly controllable and reversible active assembly of colloidal CsPbBr3 nanorods, driven by an external electric field is achieved. This approach enables the nanorods dynamically orient themselves, assemble into chains, aggregate into columns, and eventually form an ordered column array, with the electric field intensity varying from 0 to 50 V µm-1 at 100 kHz. The nanorods inside the columns align parallel to the electric field, leading to a well-ordered structure. With the analysis of the interactions among the nanorods, a quantitative interpretation of the assembly is proposed. Monte Carlo calculation is also introduced to simulate the assembly process and the results prove to be in great agreement with the experimental observations. This electric field-driven assembly presents an exciting opportunity to pave the way for next-generation sensors and photonic devices based on well-developed colloidal nanoparticles.

Electron Donor-Acceptor Complex Driven Photocatalyst-Free Trifluoromethylation of Heterocycles.

Heterocyclic trifluoromethylation is efficiently initiated through a photochemical reaction utilizing an electron donor-acceptor (EDA) complex, proceeding smoothly without the use of photocatalysts, transition-metal catalysts, or additional oxidants. This method has been optimized through extensive experimentation, demonstrating its versatility and efficacy across various substrates, including quinoxalinones, coumarins, and indolones. Notably, this approach enables the practical synthesis of trifluoromethylated quinoxalinones on a gram scale. Mechanistic investigations that incorporate radical trapping and ultraviolet/visible spectroscopy, confirmed the formation of the an EDA complex and elucidated the reaction pathways. This study highlights the crucial role of EDA photoactivation in trifluoromethylation, significantly expanding the application scope of EDA complexes in chemical synthesis.

Genome-wide association study and selective sweep analysis uncover candidate genes controlling curd branch length in cauliflower.

Cauliflower is a distinct subspecies of the Brassica oleracea plants due to its specialized and edible floral organ. Cauliflower curd is composed of enlarged inflorescence meristems that developed by a series of precise molecular regulations. Based solely on the curd solidity, cauliflower is generally classified into two groups (compact-curd and loose-curd), where curd branch length acts as a crucial parameter to determine the curd morphological difference. Herein, to understand the genetic basis of curd branch development, we utilized a total of 298 inbred lines representing two groups of cauliflower to comprehensively investigate the causal genes and regulatory mechanisms. Phylogenetic and population structure analyses revealed that two subgroups could be further categorized into the compact-curd and the loose-curd groups, respectively. Integrating the genotype and phenotype data, we conducted a genome-wide association study for the length of the outermost branch (LOB) and secondary branch (LSB) of the curd. Sixty-four significant loci were identified that are highly associated with curd branch development. Evidence from genome-wide selective sweep analysis (FST and XP-EHH) narrowed down the major signal on chromosome 8 into an approximately 79 kb region which encodes eleven protein-coding genes. After further analysis of haplotypes, transcriptome profiling, and gene expression validation, we finally inferred that BOB08G028680, as a homologous counterpart of AtARR9, might be the causal gene for simultaneously regulating LOB and LSB traits in cauliflower. This result provides valuable information for improving curd solidity in future cauliflower breeding.

Fe Crystalline Phases in Fe/C Composites Modulated the Selective Adsorption of Pb(II) from Industrial Wastewater with Cd(II): An Electronic-Scale Perspective.

Fe oxide or Fe0-based materials display weak removal capacity for Pb(II), especially in the presence of Cd(II), and the electronic-scale mechanisms are not reported. In this study, Fe3C(220) modified black carbon (BC) [Fe3C(220)@BC] with high adsorption and selectivity for Pb(II) from industrial wastewater with Cd(II) was developed. The quantitative experiment suggested that Fe species accounted for 80.5-100 and 18.4-33.8% of Pb(II) and Cd(II) removal, respectively. Based on X-ray absorption near-edge structure analysis, 57.3% of adsorbed Pb2+ was reduced to Pb0; however, 61.6% of Cd2+ existed on Fe3C@BC. Density functional theory simulation unraveled that Cd(II) adsorption was attributed to the cation-π interaction with BC, whereas that of Pb(II) was ascribed to the stronger interactions with different Fe phases following the order: Fe3C(220) > Fe0(110) > Fe3O4(311). Crystal orbital bond index and Hamilton population analyses were innovatively applied in the adsorption system and displayed a unique discovery: the stronger Pb(II) adsorption on Fe phases was mediated by a combination of covalent and ionic bonding, whereas ionic bonding was mainly accounted for Cd(II) adsorption. These findings open a new chapter in understanding the functions of different Fe phases in mediating the fate and transport of heavy metals in both natural and engineered systems.

Outdoor Radon Dose Rate in Canada's Arctic amid Climate Change.

Decades of radiation monitoring data were analyzed to estimate outdoor Radon Dose Rates (RnDRs) and evaluate climate change impacts in Canada's Arctic Regions (Resolute and Yellowknife). This study shows that the RnDR involves dynamic sources and complex environmental factors and processes. Its seasonality and long-term trends are significantly impacted by temperatures and soil-and-above water contents. From 2005 to 2022, Yellowknife's RnDR increased by +0.35 ± 0.06 nGy/h per decade, with the fastest increases occurring in cold months (October to March). The rise is largely attributable to water condition changes over time in these months, which also caused enhanced soil gas emissions and likely higher indoor radon concentrations. In Resolute, the RnDR increased between 2013 and 2022 at +0.62 ± 0.19 nGy/h (or 16% relatively) per decade in summer months, with a positive temperature relationship of +0.12 nGy/h per °C. This work also demonstrates the relevance of local climate and terrain features (e.g., typical active layer depth, precipitation amount/pattern, and ground vegetation cover) in researching climate change implications. Such research can also benefit from using supporting monitoring data, which prove effective and scientifically significant. From the perspective of external exposure to outdoor radon, the observed climate change effects pose a low health risk.

Assessment of Global Antibiotic Exposure Risk for Crops: Incorporating Soil Adsorption via Machine Learning.

The overuse and misuse of antibiotics could significantly increase their accumulation in soils. Consequently, antibiotics possibly enter food chain through crop uptake, posing a threat to global food security. Assessing the exposure risks of antibiotics for crops is crucial for addressing this global issue. In this study, we assessed global antibiotic exposure risk for crops, incorporating a machine learning adsorption model based on 4893 data sets from nine antibiotics. The optimized machine learning adsorption model, using the eXtreme Gradient Boosting algorithm and the class-specific modeling strategy, demonstrated relatively good performance. Notably, we introduced unsaturated soil conditions and considered spatiotemporal variations in soil moisture and temperature for the first time in such a risk assessment. Global distributions of antibiotic exposure risk for crops were predicted for March, June, September, and December. The results indicate that soil moisture significantly influences the exposure risk assessment. Relatively high exposure risk for crops was observed during months with colder local temperatures: generally June for the Southern Hemisphere and December for the Northern Hemisphere. The resulting map highlights high-risk agricultural regions, including southern Canada, western Russia, and southern Australia.

Study on the mechanism of Huangqi Guizhi Wuwu Decoction in treating diabetes peripheral neuropathy based on network pharmacology and molecular docking.

This study aimed to explore the effective substances and mechanism network of Huangqi Guizhi Wuwu Decoction in treating diabetes peripheral neuropathy. Based on the TCM systemic pharmacological analysis platform (TCMP) and UniProt database, the database of active Huqarqu Decoction was constructed, and the related targets of diabetic peripheral neuropathy were collected through the OMIM, CTD, DisGeNET, TTD and GeneCards databases. The intersection targets were obtained to construct the network diagram of Huangqi dis Guizhi Wuwu Decoction-Active Through the String database, the interaction between target proteins was analyzed, and molecular docking between active components and potential targets was carried out. Combined with the DAVID v6.8 database, GO function analysis and KEGG pathway analysis were performed on the targets. Guizhi Wuwu Decoction mainly acts on core targets such as IL6, MAPK3, VE GFA, JUN and ESR1 through quercetin, kaempferol and naringin and regulates the TNF signaling pathway, estrogen signaling pathway and MAPK signaling pathway, thus achieving the effect of treating diabetes peripheral neuropathy. Huangqi Guizhi Wu has multiple targets and regulates multiple signaling pathways in neuropathy, which lays a foundation for future pharmacological research.

Case report: Woven-like coronary arteries in a patient with polycythemia vera.

BACKGROUND: Woven coronary artery (WCA) is a rare and underdiagnosed congenital anomaly that involves multiple thin and tortuous epicardial arterial conduits reassembling distally into a single lumen. Recanalized thrombus may present as woven-like coronary arteries, appearing similar to WCA on angiographic images. CASE PRESENTATION: A 58-year-old female patient with intermittent chest pain for 5 years and polycythaemia vera (PV) for 8 years. The left anterior descending artery was presented like WCA on coronary angiography and finally confirmed as recanalized thrombus by optical coherence tomography(OCT), which might have been caused by PV. Given the patient's high thrombotic risk of PV and thrombotic changes in the left circumflex artery (LCX), we ultimately chose a conservative treatment without stenting. CONCLUSIONS: OCT would be needed for the diagnosis and differential diagnosis of woven-like coronary arteries. And physicians should take an appropriate treatment in a personalized way in patients with PV.

Discovery of Dehydroabietylamine Derivatives as Antibacterial and Antifungal Agents.

A diverse array of biologically active derivatives was derived by modifying the chemically active sites of dehydroabietylamine. Herein, we describe the synthesis of a new series of C-19-arylated dehydroabietylamine derivatives using a palladium-catalyzed C(sp3)-H activation reaction. Five analogues (3b, 3d, 3h, 3n, and 4a) exhibited antibacterial activity against Escherichia coli. Compound 4a exhibited strong inhibitory activity against DNA Topo II and Topo IV. Molecular docking modeling indicated that it can bind effectively to the target through interactions with amino acid residues. The synthesized compounds were tested in vitro for their antifungal activity against six common phytopathogenic fungi. The mechanism of action of compound 4c against Rhizoctorzia solani was investigated, revealing that it disrupts the morphology of the mycelium and enhances cell membrane permeability.

Balloon-Shaped SMF Blood Glucose Concentration and Temperature Sensor Based on Core-Offset Structure.

A blood glucose concentration and temperature sensor with a balloon-shaped single-mode fiber (SMF) based on a core-offset structure is proposed and experimentally demonstrated. The balloon-shaped SMF is created by offset-fusing a straight-line SMF between two other SMFs, thereby forming a Mach-Zehnder interferometer (MZI). The core-offset structure can effectively excite higher-order cladding modes. The experimental results showed that the maximum sensitivity of blood glucose concentration was 0.331 nm/(mmol/l) and the maximum sensitivity of temperature was 0.216 nm/°C when the offset distance was 10 µm. Dual-parameter measurement was achieved through a dual-parameter matrix. In addition, the sensor has characteristics such as simple structure, low cost, good stability, and electromagnetic interference resistance, making it potentially valuable for diagnosing high blood glucose and related conditions.

Smart Magnetic Optical Antenna for Automatic Nanoalignment and Photon Beaming from Prepatterned Single Quantum Dot Nanospot.

We present a unidirectional dielectric optical antenna, which can be chemically synthesized and controlled by magnetic fields. By applying magnetic fields, we successfully aligned an optical antenna on a prepatterned quantum dot nanospot with accuracy better than 40 nm. It confined the fluorescence emission into a 16-degree wide beam and enhanced the signal by 11.8 times. Moreover, the position of the antenna, and consequently the beam direction, can be controlled by simply adjusting the direction of the magnetic fields. Theoretical analyses show that this magnetic alignment technique is stable and accurate, providing a new strategy for building high-performance tunable nanophotonic devices.

The Construction of lncRNA/circRNA-miRNA-mRNA Networks Reveals Functional Genes Related to Growth Traits in Schima superba.

Schima superba is a precious timber and fire-resistant tree species widely distributed in southern China. Currently, there is little knowledge related to its growth traits, especially with respect to molecular breeding. The lack of relevant information has delayed the development of modern breeding. The purpose is to identify probable functional genes involved in S. superba growth through whole transcriptome sequencing. In this study, a total of 32,711 mRNAs, 525 miRNAs, 54,312 lncRNAs, and 1522 circRNAs were identified from 10 S. superba individuals containing different volumes of wood. Four possible regulators, comprising three lncRNAs, one circRNA, and eleven key miRNAs, were identified from the regulatory networks of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA to supply information on ncRNAs. Several candidate genes involved in phenylpropane and cellulose biosynthesis pathways, including Ss4CL2, SsCSL1, and SsCSL2, and transcription factors, including SsDELLA2 (SsSLR), SsDELLA3 (SsSLN), SsDELLA5 (SsGAI-like2), and SsNAM1, were identified to reveal the molecular regulatory mechanisms regulating the growth traits of S. superba. The results not merely provide candidate functional genes related to S. superba growth trait and will be useful to carry out molecular breeding, but the strategy and method also provide scientists with an effective approach to revealing mechanisms behind important economic traits in other species.