Dislocation flow turbulence simultaneously enhances strength and ductility.

Multi-principal element alloys (MPEAs) exhibit outstanding strength attributed to the complex dislocation dynamics as compared to conventional alloys. Here, we develop an atomic-lattice-distortion-dependent discrete dislocation dynamics framework consisted of random field theory and phenomenological dislocation model to investigate the fundamental deformation mechanism underlying massive dislocation motions in body-centered cubic MPEA. Amazingly, the turbulence of dislocation speed is identified in light of strong heterogeneous lattice strain field caused by short-range ordering. Importantly, the vortex from dislocation flow turbulence not only acts as an effective source to initiate dislocation multiplication but also induces the strong local pinning trap to block dislocation movement, thus breaking the strength-ductility trade-off.

Generalized reporter score-based enrichment analysis for omics data.

Enrichment analysis contextualizes biological features in pathways to facilitate a systematic understanding of high-dimensional data and is widely used in biomedical research. The emerging reporter score-based analysis (RSA) method shows more promising sensitivity, as it relies on P-values instead of raw values of features. However, RSA cannot be directly applied to multi-group and longitudinal experimental designs and is often misused due to the lack of a proper tool. Here, we propose the Generalized Reporter Score-based Analysis (GRSA) method for multi-group and longitudinal omics data. A comparison with other popular enrichment analysis methods demonstrated that GRSA had increased sensitivity across multiple benchmark datasets. We applied GRSA to microbiome, transcriptome and metabolome data and discovered new biological insights in omics studies. Finally, we demonstrated the application of GRSA beyond functional enrichment using a taxonomy database. We implemented GRSA in an R package, ReporterScore, integrating with a powerful visualization module and updatable pathway databases, which is available on the Comprehensive R Archive Network (https://cran.r-project.org/web/packages/ReporterScore). We believe that the ReporterScore package will be a valuable asset for broad biomedical research fields.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

Regulatory role of exosome-derived miRNAs and other contents in adipogenesis.

Intramuscular fat (IMF) content significantly impacts meat quality. influenced by complex interactions between skeletal muscle cells and adipocytes. Adipogenesis plays a pivotal role in IMF formation. Exosomes, extracellular membranous nanovesicles, facilitate intercellular communication by transporting proteins, nucleic acids (DNA and RNA), and other biomolecules into target cells, thereby modulating cellular behaviors. Recent studies have linked exosome-derived microRNAs (miRNAs) and other cargo to adipogenic processes. Various cell types, including skeletal muscle cells, interact with adipocytes via exosome secretion and uptake. Exosomes entering adipocytes regulate adipogenesis by modulating key signaling pathways, thereby influencing the extent and distribution of IMF deposition. This review comprehensively explores the origin, formation, and mechanisms of exosome action, along with current research and their applications in adipogenesis. Emphasis is placed on exosome-mediated regulation of miRNAs, non-coding RNAs (ncRNAs), proteins, lipids, and other biomolecules during adipogenesis. Leveraging exosomal contents for genetic breeding and treating obesity-related disorders is discussed. Insights gathered contribute to advancing understanding and potential therapeutic applications of exosome-regulated adipogenesis mechanisms.

Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

HK2 in microglia and macrophages contribute to the development of neuropathic pain.

Neuropathic pain is a complex pain condition accompanied by prominent neuroinflammation involving activation of both central and peripheral immune cells. Metabolic switch to glycolysis is an important feature of activated immune cells. Hexokinase 2 (HK2), a key glycolytic enzyme enriched in microglia, has recently been shown important in regulating microglial functions. Whether and how HK2 is involved in neuropathic pain-related neuroinflammation remains unknown. Using a HK2-tdTomato reporter line, we found that HK2 was prominently elevated in spinal microglia. Pharmacological inhibition of HK2 effectively alleviated nerve injury-induced acute mechanical pain. However, selective ablation of Hk2 in microglia reduced microgliosis in the spinal dorsal horn (SDH) with little analgesic effects. Further analyses showed that nerve injury also significantly induced HK2 expression in dorsal root ganglion (DRG) macrophages. Deletion of Hk2 in myeloid cells, including both DRG macrophages and spinal microglia, led to the alleviation of mechanical pain during the first week after injury, along with attenuated microgliosis in the ipsilateral SDH, macrophage proliferation in DRGs, and suppressed inflammatory responses in DRGs. These data suggest that HK2 plays an important role in regulating neuropathic pain-related immune cell responses at acute phase and that HK2 contributes to neuropathic pain onset primarily through peripheral monocytes and DRG macrophages rather than spinal microglia.

Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.

BACKGROUND: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs. METHODS: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests. RESULTS: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response. CONCLUSIONS: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.

Covalent Organic Frameworks with Tunable Chirality for Chiral-Induced Spin Selectivity.

Chiral covalent organic frameworks (CCOFs) have attracted extensive interest for their potential applications in various enantioselective processes. However, the exploitation of chirality-induced spin selectivity (CISS) that enables a new technology for the injection of spin polarized current without the need for a permanent magnetic layer within CCOFs remains a largely untapped area of research. Here, we demonstrate that, for the first time, COFs can be an attractive platform to develop spin filter materials with efficient CISS. This facilitates the design and synthesis of a new family of Zn(salen)-based 2D CCOFs, namely, CCOFs-9-12, by imine condensation of chiral 1,2-diaminocyclohexane and tri- or tetra(salicylaldehyde) derivatives. CCOF-9, distinguished by its unique C2 symmetric "armchair" tetrasubstituted pyrene conformation, exhibits the most pronounced chirality among these materials and serves as a solid-state host, enabling the enantioselective adsorption of racemic drugs with an enantiomeric excess (ee) of up to 97%. After substituting diamagnetic zinc(II) ions for paramagnetic cobalt(II), the resulting CCOF-9-Co not only retains its high crystallinity, porosity, and exceptional chirality but also exhibits enhanced conductivity, a crucial factor for the effective observation of CISS. Magnetic conductive atomic force microscopy showed that CCOF-9-Co exhibited a remarkable CISS effect with up to an 88-94% spin polarization ratio. This phenomenon is further confirmed by the increased intensity in the magnetic circular dichroism (MCD) when CCOF-9-Co is under an external magnetic field. This work therefore shows the tremendous potential of CCOFs for controlling spin selectivity and will stimulate the creation of new types of crystalline polymers with strong CISS effects for spin filters.

Mixed-Linker Chiral 2D Covalent Organic Frameworks with Controlled Layer Stacking for Electrochemical Asymmetric Catalysis.

Covalent organic frameworks (COFs) have undergone extensive research as heterogeneous catalysts for a wide range of significant reactions, but they have not yet been investigated in the realm of electrochemical asymmetric catalysis, despite their recognition as an economical and sustainable strategy for producing enantiopure compounds. Here, we report a mixed-linker strategy to design multicomponent two-dimensional (2D) chiral COFs with tunable layer stacking for highly enantioselective electrocatalysis. By crystallizing mixtures of triamines with and without the MacMillan imidazolidinone catalyst or aryl substituent (ethyl and isopropyl) and a dialdehyde derivative of thieno-[3,2-b]thiophene, we synthesized and structurally characterized a series of three-component homochiral 2D COFs featuring either AA or ABC stacking. The stacking modes that can be synthetically controlled through steric tuning using different aryl substituents affect their chemical stability and electrochemical performance. With the MacMillan catalyst periodically appended on their channels, all three COFs with conductive thiophene moieties can be highly enantioselective and recyclable electrocatalysts for the asymmetric α-arylation of aldehydes, affording alkylated anilines with up to 97% enantiomeric excess by an anodic oxidation/organocatalytic protocol. Presumably due to their higher charge transfer ability, the ABC stacking COFs exhibit improved reactivity compared to the AA stacking analogue. This work therefore advances COFs as electrocatalysts for asymmetric catalysis and may facilitate the design of more redox-active crystalline organic polymers for electrochemical enantioselective processes.

Quantum Dot-Based Three-Dimensional Single-Particle Tracking Characterizes the Evolution of Spatiotemporal Heterogeneity in Necrotic Cells.

Cell death is a fundamental biological process with different modes including apoptosis and necrosis. In contrast to programmed apoptosis, necrosis was previously considered disordered and passive, but it is now being realized to be under regulation by certain biological pathways. However, the intracellular dynamics that coordinates with cellular structure changes during necrosis remains unknown, limiting our understanding of the principles of necrosis. Here, we characterized the spatiotemporal intracellular diffusion dynamics in cells undergoing necrosis, using three-dimensional single-particle tracking of quantum dots. We found temporally increased diffusion rates in necrotic cells and spatially enhanced diffusion heterogeneity in the cell periphery, which could be attributed to the reduced molecular crowding resulting from cell swelling and peripheral blebbing, respectively. Moreover, the three-dimensional intracellular diffusion transits from strong anisotropy to nearly isotropy, suggesting a remodeling of the cytoarchitecture that relieves the axial constraint on intracellular diffusion during necrosis. Our results reveal the remarkable alterations of intracellular diffusion dynamics and biophysical properties in necrosis, providing insight into the well-organized nonequilibrium necrotic cell death from a biophysical perspective.

Orthostatic blood pressure changes do not influence cognitive outcomes following intensive blood pressure control.

BACKGROUND: Effects of intensive blood pressure (BP) control on cognitive outcomes in patients with excess orthostatic BP changes are unclear. We aimed to evaluate whether orthostatic BP changes modified the effects of BP intervention on cognitive impairment. METHODS: We analyzed 8547 participants from the Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension. Associations between orthostatic BP changes and incident cognitive outcomes were evaluated by restricted cubic spline curves based on Cox models. The interactions between orthostatic BP changes and intensive BP intervention were assessed. RESULTS: The U-shaped associations were observed between baseline orthostatic systolic BP changes and cognitive outcomes. However, there were insignificant interactions between either change in orthostatic systolic BP (P for interaction = 0.81) or diastolic BP (P for interaction = 0.32) and intensive BP intervention for the composite outcome of probable dementia or mild cognitive impairment (MCI). The hazard ratio of intensive versus standard target for the composite cognitive outcome was 0.82 (95% CI 0.50-1.35) in those with an orthostatic systolic BP reduction of >20 mmHg and 0.41 (95% CI 0.21-0.80) in those with an orthostatic systolic BP increase of >20 mmHg. Results were similar for probable dementia and MCI. The annual changes in global cerebral blood flow (P for interaction = 0.86) consistently favored intensive BP treatment across orthostatic systolic BP changes. CONCLUSION: Intensive BP control did not have a deteriorating effect on cognitive outcomes among hypertensive patients experiencing significant postural BP changes.

Island-Like Heterogeneous Interface Generating Tandem Toroidal Built-In Electric Field for Efficient Potassium Ions Diffusion.

For large-size potassium accommodation, heterostructure usually suffers severe delamination and exfoliation at the interfaces due to different volume expansion of two-phase during charge/discharge process, resulting in the deconstruction of heterostructures and shortened lifespan of batteries. Here, an innovative strategy is proposed through constructing a microscopic heterostructure system containing copper quantum dots (Cu QDs) highly dispersed in the triphenyl-substituted triazine graphdiyne (TPTG) substrates (TPTG@CuQDs) to solve this problem. The copper quantum dots are uniformly anchored on TPTG substrates, generating a myriad of island-like heterogeneous structures, together with tandem toroidal built-in electric field (BIEF) between every micro heterointerface. The island-like heterostructure endows both benefits of exposed contact interface and robust architecture. Generated tandem toroidal BIEF provides efficient transport pathways with lower energy barriers, reducing the diffusion resistance and facilitating the reaction kinetics of potassium ions. When used as anode, the TPTG@CuQDs exhibit highly reversible capacity and low-capacity degradation (≈0.01% over 5560 cycles at 1 A g-1). Moreover, the TPTG@CuQDs-based full cell delivers an outstanding reversible capacity of ≈110 mAh g-1 over 800 cycles at 1 A g-1. This quantum-scale heterointerface construction strategy offers a new approach toward stable heterostructure design for the application of metal ion batteries.

From pixels to patient care: deep learning-enabled pathomics signature offers precise outcome predictions for immunotherapy in esophageal squamous cell cancer.

BACKGROUND: Immunotherapy has significantly improved survival of esophageal squamous cell cancer (ESCC) patients, however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&E-stained pathological specimens to accurately predict the clinical benefit of PD-1 inhibitors in ESCC patients. METHODS: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. WSI images of H&E-stained histological specimens of included patients were collected, and randomly divided into training (70%) and validation (30%) sets. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. RESULTS: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&E-stained histological specimens after image pre-processing. There were 120 patients with 227 images in training cohort and 43 patients with 97 images in validation cohort, with balanced baseline characteristics between two groups. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.6, 4.5 and 12.9 months (P < 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P < 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.904, 0.924, 0.610 for 6-month PFS and C-index of 0.814, 0.806, 0.601, respectively. CONCLUSIONS: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.

Macrophage-derived PDGF-BB modulates glycolytic enzymes expression and pyroptosis in nucleus pulposus cells via PDGFR-ß/TXNIP pathway.

OBJECTIVE: Intervertebral Disc Degeneration (IVDD) is one of the leading causes of low back pain, significantly impacting both individuals and society. This study aimed to investigate the significance of macrophage infiltration and the role of macrophage-secreted platelet-derived growth factor-BB (PDGF-BB) in IVDD progression. METHODS: To confirm the protective function of macrophage-derived PDGF-BB on nucleus pulposus cells (NPCs), we employed Lysm-Cre transgenic mice to genetically ablate PDGF-B within the myeloid cells. Immunohistochemistry was utilized to detect the expression of glycolytic enzymes and pyroptosis-related proteins during the process of IVDD. Western blot, RT-PCR, ELISA and immunofluorescence were used to detect the protective effect of recombinant PDGF-BB on NPCs. RESULTS: Macrophage-derived PDGF-BB deficiency resulted in the loss of NPCs and the increased ossification of cartilage endplates during lumbar disc degeneration. Also, PDGF-BB deficiency triggered the inhibition of glycolytic enzymes' expression and the activation of pathways related to pyroptosis in the nucleus pulposus. Mechanistically, our results suggest that PDGF-BB predominantly conveys its protective influence on NPCs through the PDGF receptor- beta (PDGFR-ß)/ thioredoxin-interacting protein pathway. CONCLUSIONS: The absence of PDGF-BB originating from macrophages expedites the advancement of IVDD, whereas the application of PDGF-BB treatment holds the potential for retarding intervertebral disc degeneration in the human body.

Phonon Thermal Transport in UO_{2} via Self-Consistent Perturbation Theory.

Computing thermal transport from first-principles in UO_{2} is complicated due to the challenges associated with Mott physics. Here, we use irreducible derivative approaches to compute the cubic and quartic phonon interactions in UO_{2} from first principles, and we perform enhanced thermal transport computations by evaluating the phonon Green's function via self-consistent diagrammatic perturbation theory. Our predicted phonon lifetimes at T=600 K agree well with our inelastic neutron scattering measurements across the entire Brillouin zone, and our thermal conductivity predictions agree well with previous measurements. Both the changes due to thermal expansion and self-consistent contributions are nontrivial at high temperatures, though the effects tend to cancel, and interband transitions yield a substantial contribution.

Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase.

BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression.

BACKGROUND: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. METHODS: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. RESULTS: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. CONCLUSIONS: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.

Cascade 1,3-Diploar Cycloaddition and Lactamization for Diastereoselective Synthesis of Pyrrolidinedione-Fused Tetrahydropyrroloisoindolones.

A cascade reaction sequence of 1,3-dipolar cycloaddition and lactamization for the synthesis of tetrahydropyrroloisoindolone derivatives is developed. This efficient one-pot synthesis generates four bonds and two heterocyclic rings in a diastereoselective manner. Only 2 equiv of H2O are produced as the side product.

Palladium-Catalyzed C(sp3)-H Nitrooxylation of Aliphatic Carboxamides with Practical Oxidants.

Here we report the palladium-catalyzed ß-C(sp3)-H nitrooxylation of aliphatic carboxamides using a modified quinoline auxiliary. Notably, Al(NO3)3·9H2O was used as a nitrate source as well as a practical oxidant. The 5-chloro-8-aminoquinoline auxiliary was nitrated in situ during the reaction, which may enhance its directing ability and help its removal. The reaction has a broad substrate scope with a variety of aliphatic carboxamides. The multiple substituted auxiliary can be easily removed and recovered. Two C-H-insertion palladacycle intermediates were isolated and characterized to elucidate the mechanism.

Longitudinal Mapping of Personal Biotic and Abiotic Exposomes and Transcriptome in Underwater Confined Space Using Wearable Passive Samplers.

Silicone-based passive samplers, commonly paired with gas chromatography-mass spectrometry (GC-MS) analysis, are increasingly utilized for personal exposure assessments. However, its compatibility with the biotic exposome remains underexplored. In this study, we introduce the wearable silicone-based AirPie passive sampler, coupled with nontargeted liquid chromatography with high-resolution tandem mass spectrometry (LC-HRMS/MS), GC-HRMS, and metagenomic shotgun sequencing methods, offering a comprehensive view of personalized airborne biotic and abiotic exposomes. We applied the AirPie samplers to 19 participants in a unique deep underwater confined environment, annotating 4,390 chemical and 2,955 microbial exposures, integrated with corresponding transcriptomic data. We observed significant shifts in environmental exposure and gene expression upon entering this unique environment. We noted increased exposure to pollutants, such as benzenoids, polycyclic aromatic hydrocarbons (PAHs), opportunistic pathogens, and associated antibiotic-resistance genes (ARGs). Transcriptomic analyses revealed the activation of neurodegenerative disease-related pathways, mostly related to chemical exposure, and the repression of immune-related pathways, linked to both biological and chemical exposures. In summary, we provided a comprehensive, longitudinal exposome map of the unique environment and underscored the intricate linkages between external exposures and human health. We believe that the AirPie sampler and associated analytical methods will have broad applications in exposome and precision medicine.