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A Versatile Tumor Microenvironment-Responsive Nanoprobe for Cancer Screening and Early Detection
Abstract It has been highly challenging to reliably detect various cancers at an early stage when tumors are just millimeters in size. To address this, we developed a tumor microenvironment (TME)-responsive nanoprobe, PR-KAd@CD-AuNC, enabling cross-validated cancer detection through in vivo second near-infrared (NIR-II) fluorescence imaging and in vitro colorimetric urinalysis. The nanoprobe consists of three integrated components: a renal-clearable signal-output segment (cyclodextrin-functionalized gold nanocluster, CD-AuNC), a tumor-targeting and size-controlling component (PR), and a matrix metalloproteinase-2 (MMP2)-cleavable linker (KAd). PR, composed of 8-arm poly(ethylene glycol) for prolonged circulation and c(RGDfK) peptides for αvβ3 integrin targeting, directed selective tumor accumulation after intravenous injection of PR-KAd@CD-AuNC. The intrinsic emission of CD-AuNC above 1100 nm enabled high-resolution, real-time NIR-II fluorescence imaging with attenuated photon scattering, allowing precise tumor delineation. Within the TME, specifically overexpressed MMP2 cleaved the KAd linker, releasing ∼2 nm CD-AuNC fragments from the ∼10 nm parent nanoprobe. Being smaller than the ∼5.5 nm renal filtration threshold, these fragments were renally excreted. Concurrently, the peroxidase-like activity of CD-AuNC catalyzed tetramethylbenzidine oxidation to produce a visible blue signal, providing a simple and low-cost urinalysis method suitable for broad cancer screening applications. This dual-modality strategy effectively distinguished cancers from inflammation and other diseases, detecting small tumors for multiple cancer types with a sensitivity surpassing that of computed tomography (CT) imaging, which makes it a promising early detection approach. Furthermore, it was also employed to dynamically assess cancer therapeutic efficacy (i.e., immunotherapy, chemotherapy, and surgical resection), suggesting clinical value for guiding treatment decisions.
Perceptions of Spanish-language COVID-19 video messaging among the Hispanic community: A qualitative study in the United States of America
With evidence linking credible and quality COVID-19 vaccine information to positive vaccination attitudes and intentions, it's vital to understand how communities facing health disparities access health information about COVID-19. This interview study of 49 Hispanic individuals in a large southern suburban county is a part of a larger three-year multi-method study. Through the lens of self-determination theory, this project investigates perceptions of four television-aired Spanish-language video messages on CseOVID-19 vaccination developed from findings of prior local focus groups and panel surveys supported by community partners. The present study’s findings show human-centered, gain-frame messaging was positively received and highlight the need for targeted Spanish-language public health messaging in Spanish news media to improve quality information about COVID-19. Gentler suggestions for health protective behaviors may foster greater perceived resonance, credibility, and informational value of public health messages, with potential implications for psychological reactance and subsequent responses.
Coupling Photochromism and Charge Transport in π-Extended Arylazo Oligothiophenes and Oligothienoacenes
Abstract Developing photoresponsive molecular materials that couple efficient charge transport with robust photoswitching remains challenging because structural features enhancing one function often compromise the other. In this study, two homologous series of arylazo oligothiophenes and oligothienoacenes–in which an azo photoswitch is directly conjugated to a π-extended thiophenic scaffold–were systematically investigated. Ultraviolet–visible (UV–vis) spectroscopy combined with theoretical calculations shows that, in solution, π-extension enables E → Z photoisomerization using visible light but concurrently lowers the barrier for thermal Z → E back-conversion by activating rotational isomerization pathways. Aryl fluorination counteracts this effect by strengthening intramolecular S(n)···π interactions, extending the Z-isomer half-life from minutes to hours. In the solid state, π-extension promotes dense intermolecular packing that inhibits photoisomerization. Introduction of a bulky trityl group reduces packing density, as revealed by single-crystal analysis, restoring E ⇆ Z photochromism in crystalline thin films and inducing a crystalline-to-amorphous transformation, as evidenced by X-ray diffraction (XRD) and microscopic analysis. The resulting light-driven molecular and morphological reorganization enables reversible, light-induced modulation of electrical conductivity in two-contact planar devices. Space-charge-limited-current measurements show that conductivity changes correlate with isomer-dependent electron mobility properties. Overall, these findings establish π-extended azo-thiophene scaffolds as a versatile platform to couple photochromism and morphological reorganization with charge transport phenomena.
Association between occupational hearing loss and predicted 10 year cardiovascular risk among middle aged industrial workers
Purpose Occupational hearing loss is a prevalent occupational disease with potential systemic health implications, including cardiovascular disease (CVD). This cross-sectional study investigated the association between hearing loss and 10-year CVD risk among middle-aged industrial workers in Tehran. Methods A total of 988 workers (83.7% male, mean age 46.8 ± 5.9 years) underwent routine occupational health examinations, including pure-tone audiometry and cardiovascular risk assessment using the WHO/ISH prediction chart. Hearing-loss phenotypes included low-frequency hearing loss (LFHL), high-frequency hearing loss (HFHL), overall hearing loss (HL), and noise-induced hearing loss (NIHL). Ear-specific hearing loss was first assessed separately for the left and right ears; participant-level hearing-loss variables were then defined based on the presence of hearing loss in either ear. The WHO/ISH 10-year CVD risk score was reported descriptively. To avoid conceptual overlap between the composite WHO/ISH score and its component variables, the composite CVD-risk variable was not entered into multivariable logistic regression models. Instead, multivariable logistic regression was used to identify demographic, occupational, and clinical factors associated with each hearing-loss phenotype. Results The prevalence of NIHL was 19.9%. Ear-specific HFHL was observed in 27.2% of left ears and 25.5% of right ears, while LFHL was observed in 17.0% of left ears and 18.0% of right ears. In multivariable logistic regression models, sex and age were the most consistent independent factors associated with hearing loss. Female sex was associated with lower odds of LFHL, HFHL, overall HL, and NIHL compared with male sex. Older age was independently associated with LFHL, HFHL, and overall HL. Smoking was independently associated with HFHL and NIHL, while work experience was independently associated with NIHL. Job type and diabetes were not consistent independent predictors in the adjusted models. The composite WHO/ISH CVD-risk score was not included in the adjusted models to avoid conceptual overlap with its component variables. Conclusion These findings highlight the importance of demographic, behavioral, and occupational factors, particularly sex, age, smoking, and work experience, in occupational hearing loss among middle-aged industrial workers. Although predicted 10-year CVD risk was described in this occupational cohort, the composite WHO/ISH risk score was not included in multivariable models together with its component variables. Hearing conservation programs should integrate noise control, regular audiometric screening, smoking cessation, and cardiovascular risk assessment as complementary components of occupational health surveillance.
The effect of a multimodal multicomponent Prehabilitation program in Older adults with Chronic limb-threatening Ischemia (POCI-study): A study protocol for a multicenter randomized controlled trial
Chronic limb threatening ischemia (CLTI) in older adults is associated with severe morbidity and high mortality. The rising prevalence is largely driven by the aging population and confronts healthcare systems with challenges like increasing demand for chronic care, staff shortage and rising healthcare costs. To improve post-operative outcomes and reduce the burden on healthcare systems, multimodal prehabilitation has gained interest and has the potential to improve post operative outcomes. However, evidence of the effect in older adults with CLTI remains scarce. The aim of this study is to determine whether a multimodal multicomponent prehabilitation program (MMPP) reduces length of stay and improves clinical, patient-reported and economic outcomes of older adults with CLTI. We developed a multicenter randomized controlled trial, with embedded cost-effectiveness analyses.. CLTI-patients aged 65 years or older, planned for revascularization, and their primary informal caregiver (IC) will be eligible. A total of 300 patients will be randomized to receive either standard preoperative care or a 2-week MMPP. All patients receive a general health screening. The MMPP includes physiotherapy and, if indicated, referral to a geriatrician, dietician or smoking-cessation coach, ferric carboxymaltose infusion or pre-arranged homecare. The primary outcome is length of stay. Exploratory secondary outcomes include minor complications, quality of life of patient and IC and health related quality of life. Descriptive secondary outcomes include 30-day and 6-month mortality, major complications, readmissions, burden on the IC, cost-effectiveness; and experiences and preferences regarding shared decision making. To the best of our knowledge, this is the first randomized controlled trial to evaluate the effect of an MMPP within older CLTI-patients. Findings will inform healthcare professionals whether an MMPP should be implemented in routine vascular surgical practice to reduce length of stay and improve clinical and patient-centered outcomes. The study is registered at the International Clinical Trials Registry Platform (NL-OMON58069).
An Iron(V)-Oxo TAML Radical Cation Complex in Photocatalytic Water Oxidation and Electron-Transfer Reactions
Abstract Iron(V)-oxo complexes have been proposed as critical reactive intermediates in catalytic water oxidation. However, iron-oxo complexes bearing redox-active (noninnocent) ligands with a formal oxidation state exceeding +5 have remained elusive. Herein, we report that an iron(V)-oxo complex bearing a one-electron oxidized tetraamido macrocyclic ligand, [FeV(O)(TAML•+)], effectively oxidizes water to evolve dioxygen (O2) via O–O bond formation. The precursor [FeIII(TAML)]− complex acts as an effective catalyst for the photochemical oxidation of water by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Transient absorption measurements reveal a stepwise, photodriven pathway: [FeIII(TAML)]− and DDQ first generate [FeV(O)(TAML)]− via a μ-oxo dimer intermediate, [(TAML)FeIV(O)FeIV(TAML)]2–. Subsequent electron transfer (ET) to the triplet excited state of DDQ (3DDQ*) yields the [FeV(O)(TAML•+)] intermediate and DDQ•–. In the presence of water, this complex reacts to produce a presumed [FeIV(OOH)(TAML)]− intermediate. The rate constants of the reaction of [FeV(O)(TAML•+)] with H2O and D2O at 298 K are determined to be 1.4 × 106 and 7.1 × 105 M–1 s–1, respectively, giving a deuterium kinetic isotope effect (KIE) of 2.0. In ET reactions, [FeV(O)(TAML•+)] is a highly reactive oxidant with an extremely small reorganization energy (λ = 0.80 eV). Such a small reorganization energy is ascribed to the TAML ligand-centered ET reduction of [FeV(O)(TAML•+)]. To the best of our knowledge, this iron(V)-oxo TAML radical cation complex, [FeV(O)(TAML•+)], represents one of the most powerful high-valent iron-oxo oxidants identified to date in water oxidation and electron transfer reactions.
An integrated Gaussian–Probabilistic–Fuzzy framework for health assessment and remaining useful life prediction of medium-voltage switchgears
Reliable operation of Switchgear is crucial for ensuring the safety and stability of modern power systems. However, prolonged exposure to thermal, mechanical, and electrical stresses progressively deteriorates switchgear performance, often resulting in catastrophic failures and costly outages. This paper proposes a novel hybrid framework for comprehensive health assessment and remaining useful life (RUL) prediction of medium-voltage (MV) switchgears by integrating Gaussian normalization, probabilistic modeling, and fuzzy logic evaluation. Initially, all measured indicators are systematically classified into four functional subsystems, electrical, mechanical, insulation, and auxiliary, to enable structured condition evaluation. The Gaussian method normalizes heterogeneous indicator values, the probabilistic approach quantifies the failure likelihood of each indicator, and the fuzzy logic system handles uncertain and linguistic expert information. The resulting subsystem health indices are aggregated to derive a global health index (HI), which is then used to estimate RUL through a (Gaussian, Probability, Fuzzy) GPF-based algorithm. The proposed framework has been validated using real field data collected from two MV substations, and its performance has been benchmarked against existing techniques. Results demonstrate superior accuracy, robustness, and interpretability of the proposed method under uncertainty, providing actionable insights for condition-based maintenance scheduling and risk-informed decision-making in power utilities.
One-Step Integration of Sulfonated Polymer Films with Separators for Shuttle Mitigation in Lithium–Sulfur Batteries
Abstract Interfacial polymerization (IP) offers a rapid and inexpensive method for fabricating thin polymer films. In this work, a one-step IP reaction between a triacyl chloride monomer and sulfonated diamine monomer is employed to add a dense, charge-selective sulfonated thin-film coating onto a commercial separator to improve selective transport in lithium–sulfur batteries. The coating effectively suppresses polysulfide shuttling, enhancing capacity retention, although at the expense of compromised rate performance due to hindered lithium conduction through the dense film. Fractional substitution of the trifunctionalized acyl chloride monomer for a difunctionalized analogue reduces the film cross-link density, which improves rate performance but decreases uniformity in film coverage. Uniform film coverage is achieved upon addition of a small fraction (0.25 wt %) of higher reactivity, nonsulfonated diamine in the IP reaction. This optimized thin film coating breaks the rate-capacity retention trade-off, enabling a capacity of 711.6 mAh g–1 after 200 cycles at 0.5C while still reaching over 800 mAh g–1 during rate testing at 2C.
Cancer surgical outcome study in Ethiopia: A 7-day multicenter prospective observational cohort study
Background Safe surgery is a fundamental quality indicator within the global surgery framework. Postoperative complications remain a leading global cause of disability, mortality, and economic loss, with a disproportionate impact on low- and middle-income countries (LMICs). Objective This study aims to generate robust epidemiological data on postoperative outcomes of cancer surgery in Ethiopia. Methods This study employed a 7-day national observational prospective cohort design. The study enrolled adult patients aged 18 years and older who underwent either elective or non-elective cancer surgery in hospitals across Ethiopia. Statistical analysis included descriptive statistics, chi-square tests for categorical variables, and logistic regression models to identify risk factors for postoperative complications. Outcome measures 7 th day postoperative mortality and complications. Statistical significance was set at p < 0.05. Results A total of 265 cancer surgeries were performed across 46 hospitals (overall surgeries = 4412). The mean patient age was 46.6 years (SD = 14.9). The majority of patients were classified as low-risk America Society of Anesthesiologists (ASA) physical status classification: ASA I (106/265, 40%) and ASA II (133/265, 50.2%) and low Eastern Cooperative Oncology Group (ECOG) performance status: ECOG 0 (112/265, 42.3%) and ECOG 1 (98/265, 37%). Colorectal cancer surgery was the most common type (38/265, 14.5%), while laparoscopic surgery was performed in only 3/265 cases (1.1%). Postoperative complications developed in 84 of 265 patients (31.7%) with leading complication was superficial surgical site infection 47/265(17.8%). Emergency surgery (AOR = 3.1, 95% CI: 1.1–8.4, p = 0.003), comorbidity (AOR = 2.0, 95% CI: 1.1–3.7, p = 0.025), and an ECOG performance status of III (AOR = 9.5, 95% CI: 1.5–61.1, p = 0.02) were statistically significantly associated with 7 th day postoperative complications. The overall 7-day mortality rate after cancer surgery was 5/265 (1.9%). Conclusion Despite the relatively young age of patients, their low ASA physical status scores, and good ECOG performance, a significant proportion experienced adverse outcomes following cancer surgery: one in three patients developed postoperative complications, one in nine required reoperations, and one in 53 died. These findings suggest a critical need for evidence-based interventions to strengthen the underlying infrastructure and care processes within the surgical system which are essential to achieving safe, effective, and high-quality surgical care for cancer patients in Ethiopia.
Reduction Inverts the Thermodynamics of the Stone–Wales Rearrangement
Abstract We demonstrate that alkali-metal doping of polycyclic aromatic hydrocarbons can reshape the potential energy surface in favor of an isomer that is disfavored in the neutral state. This effect enables an efficient inverse Stone–Wales rearrangement at temperatures as low as 250 °C for potassium-, rubidium-, and cesium-doped systems. In contrast, lithium and sodium doping exclusively promote cyclodehydrogenation at cove regions. Supported by density functional theory, we propose a mechanistically consistent pathway and report the isolation and characterization of key anionic intermediates by single-crystal X-ray diffraction, UV–vis spectroscopy, and magnetometry. These findings highlight how reduction can unlock otherwise inaccessible rearrangements in aromatic systems and inform our understanding of the functionalization of graphene, carbon nanotubes, and fullerenes.
Scope of Ni(II)-Catalyzed Nonalternating Ethylene/Carbon Monoxide Copolymerization
Abstract The recent achievement of a nonalternating ethylene/carbon monoxide (CO) copolymerization was a long-sought breakthrough. Their in-chain keto functional groups endow the resulting polyethylenes (keto-PEs) with photodegradability. To date, only two types of catalysts, based on long-known structural motifs, are capable of this challenging copolymerization to keto-PE materials, raising the question whether the reaction is restricted to this narrow scope. Here, we report a diverse range of neutral Ni(II) complexes provides access to keto-PEs, including a phosphine imidate Ni(II) catalyst that is competitive with state-of-the-art catalysts and a N-heterocyclic-carbene (NHC) phenolate Ni(II) catalyst with exceptional preference for ethylene vs CO incorporation. Density functional theory (DFT) calculations rationalize the observed selectivity for nonalternating and alternating chain growth from the individual catalysts’ activation barrier differences ΔΔG‡ and identify the strong trans-effect of the [NHC,O]-ligand and its high steric hindrance as origins of the desirable exceptionally low preference for CO incorporation.
Electrochemical Nitrate Reduction with Low-Index Cu Single Crystals: Selectivity Trends in Alkaline Solution
Abstract Electrochemical nitrate (NO3−) reduction is a promising pathway toward the production of ammonia (NH3). While copper (Cu) electrodes are commonly used for this reaction, the influence of Cu surface structure on reaction selectivity is poorly understood. Here, we performed electrochemical NO3− reduction in alkaline electrolytes with Cu(100), Cu(110), and Cu(111) single-crystal electrodes and quantified the product distributions across a range of applied potentials. Our systematic study of electrocatalytic NO3− reduction demonstrated that the Cu(100) and Cu(110) surfaces exhibited similar selectivity and rates for NH3 production, but the Cu(100) surface provided &gt;95% Faradaic efficiency toward NH3 over the broadest range of applied potentials. In contrast, the Cu(111) surface was significantly less selective for NH3 production. Further comparing the electrochemical behavior of Cu single crystals to their corresponding product distributions revealed that nitrite (NO2−) reduction voltammograms were strong predictors of electrocatalytic performance for all three low-index Cu surfaces in alkaline electrolytes. Quantum mechanical calculations indicate that the Cu(100) surface exhibits the lowest potential-determining step for NO3− reduction to NH3, supporting our experimental findings. Detailed analysis of metal−adsorbate interactions also revealed the role of Cu surface structure in stabilizing key reaction intermediates to promote selective NH3 production. Our combined experimental and computational study establishes electrocatalytic selectivity of low-index Cu facets for NH3 synthesis and offers practical guidelines for the design of Cu-based electrocatalysts capable of selective electrochemical NO3− reduction in alkaline solutions.
Two Mechanisms One Molecule: Developing a ‘Truly’ Bifunctional Degrader Targeting Rpn13 and CRBN
Abstract Targeted protein degradation (TPD) has emerged as a powerful strategy to eliminate disease-relevant proteins, yet current approaches remain largely constrained to hijacking ubiquitin ligases. We previously introduced ByeTACs, bifunctional molecules that directly recruit proteins to the proteasome for E-ligase independent degradation. Here, we report “Truly” degraders, a new class of dual-mechanism molecules that combine a ligand for the proteasomal receptor Rpn13 with a ligand for cereblon (CRBN) to simultaneously engage both ubiquitin-independent and ubiquitin-dependent degradation pathways. Structure-guided design identified an optimal linker length that supports efficient substrate processing, with the PEG4 derivative (Truly-4) inducing robust depletion of both Rpn13 and CRBN in several cancer cell types. Remarkably, Truly-4 is the first noncovalent small molecule shown to degrade full-length Rpn13, a target previously approached using covalent or domain-restricted strategies. Mechanistic studies confirmed that degradation of Rpn13 proceeds via CRBN-dependent E3 ligase activity, whereas CRBN degradation occurs through an E-ligase independent process, consistent with a ByeTAC mechanism. Importantly, Truly-4 induces selective cytotoxicity in hematologic and solid cancer cell lines but not in healthy cells, despite comparable Rpn13 depletion, indicating that dual degradation can uncouple target engagement from toxicity. These findings establish a generalizable framework for engineering bifunctional degraders that program the proteasome to execute parallel degradation mechanisms and highlight proteasome receptors as druggable nodes for selective destruction of disease-relevant proteins.
Influence of Primary Coordination Sphere on Anion Rebound Selectivity in Nonheme Fe Enzyme-Catalyzed C(sp3)–H Functionalization: A Comparative Experimental and Computational Study of EgtB and ACCO
Abstract Developing enzymatic mechanisms for C–F bond formation remains a long-standing challenge. Here, we repurposed the biosynthetic nonheme Fe enzyme EgtB, which features a three-histidine facial triad, to catalyze C(sp3)–H fluorination reactions. Directed evolution of EgtB afforded two new-to-nature fluorine atom transferases with opposite enantiopreference, EgtBCHF1 and EgtBCHF2, with up to 28-fold improved total activity. In contrast to our previously evolved nonheme Fe fluorine atom transfer biocatalyst ACCOCHF, which contains a two-histidine-one-carboxylate facial triad, the evolved EgtBCHF variants displayed unexpected hydroxylation activity. 18O-labeling experiments showed that the hydroxy group originated from water rather than residual O2. Computational studies suggested that the three-histidine-supported Fe(III) center exhibits enhanced Lewis acidity compared to the two-histidine-one-carboxylate system, allowing deprotonation of Fe(III)-bound water to form a Fe(III)–OH species that catalyzes radical hydroxylation. Primary coordination-sphere mutagenesis in EgtB and ACCO further supported the critical role of Fe coordination chemistry in controlling radical rebound reactivity and selectivity. Computational studies revealed that Fe coordination chemistry strongly influences both fluorine atom abstraction and radical rebound, with the intrinsic C–X (X = F, OH, and N3) bond forming radical rebound preference following the order N3 &gt; OH &gt; F. Furthermore, multivariate linear regression analysis revealed that fluorine atom abstraction is primarily governed by the intrinsic Fe–F bond strength, whereas fluorine rebound is predominantly controlled by the electronic structure of the Fe(III) intermediate. Together, these findings provide mechanistic insights into nonheme Fe enzymology and reprogramming toward selective radical rebound reactions, including challenging C–H fluorination.
Bidirectional Chemo-Mechanical Interface Stabilization in Perovskite Solar Cells
Abstract The interface structures between dissimilar layers in perovskite solar cells (PSCs) are prone to the concurrent occurrence of lateral (in-plane) chemical aggregation and vertical (out-of-plane) mechanical delamination. This issue severely affects long-term optoelectronic processes in PSCs, and it has not been addressed holistically. Herein, we introduce an ultrathin interfacial layer of 1,3,6,8-pyrenetetrasulfonic tetrasodium salt (PTS) to stabilize the perovskite/C60 interface at the molecular level. The sulfonate groups in PTS molecules anchor to the perovskite interface, while the parallelly aligned pyrene cores establish robust π–π interactions with C60 molecules. The reconstructed interface enhances the interfacial adhesion and restricts the mobility of C60 molecules, enabling a bidirectional chemo-mechanical interface stabilization (BCIS) mechanism at the perovskite/C60 interface. The resultant PSCs deliver power conversion efficiencies (PCEs) of up to 26.53%, showing 96% PCE retention after 1,000 h maximum-power-point tracking (ISOS-L-1l), and 91% PCE retention after 300 thermal cycles (−40 to 85 °C, IEC61215 MQT11). The scalability of PTS treatment is demonstrated by the 818 cm2 (aperture area) perovskite solar modules (PSMs) with PCEs over 20% using industrial-compatible manufacturing processes under 55% relative humidity (RH). This work underscores bidirectional interface engineering as a critical strategy for advancing commercially viable perovskite photovoltaics.
Role of Coordination Environment in Synergistic Catalysis: A Molecular Orbital Perspective on M1M2N6 Catalysts
Abstract Visualizing the coordination environment-dependent synergistic mechanisms that govern the structural stability and adsorption behavior of dual-atom catalysts (DACs) is pivotal for precise catalyst design. However, insights into these mechanisms at the molecular orbital level remain elusive. Herein, we present large-scale density functional theory calculations to elucidate how synergistic effects arise from the combination of d atomic orbitals into molecular orbitals between M1 and M2 sites, with notable variations observed from M1–N3–M2–N3–C to M1–N4–M2–N4–C. We identify an average weakening of M1/M2–N bond strength in M1–N3–M2–N3–C relative to M1–N4–M2–N4–C, which is attributed to a shift from direct dx2–y2 orbital overlap to nitrogen-mediated interactions involving the hybridization of bridge nitrogen 2p orbitals. Using hydrogen as a model adsorbate, we demonstrate that hydrogen adsorption on M1–N3–M2–N3–C shifts from wild modulation via a bridge configuration to mild modulation through an end-on configuration, signifying a selective orbital coupling from dx2–y2 to dz2 orbitals. In contrast, hydrogen adsorption on M1–N4–M2–N4–C exhibits only mild modulation via an end-on configuration. This behavior is ascribed to the symmetry constraints of antibonding (d-d/d*)-p* molecular orbitals near the Fermi level, mediated by nitrogen-mediated dz2-dz2* molecular orbitals. Furthermore, machine learning analyses corroborate these coordination environment-dependent synergistic mechanisms. Our findings provide a comprehensive molecular orbital-level understanding of how the interplay between coordination environments and electronic structures influences the properties of M1M2N6 catalysts, thereby establishing a theoretical framework for enhanced DACs design.
Pd/Mo-Catalyzed <i>ortho</i> -Dihydroxylation of Aromatic Rings: Dual-Metal-Mediated C(sp2)–H Functionalization
Abstract We report a direct ortho-dihydroxylation protocol of benzoic acids using a Pd/Mo bimetallic catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant. The Mo component significantly promotes the dihydroxylation reaction, especially the second hydroxylation step, by boosting the oxidative capacity of TBHP and presumably facilitating the oxidative addition process of Pd–Ar σ-intermediate. Mechanistic studies, including radical inhibition experiments, spectroscopic analyses, and substituent effect evaluations, reveal that Mo most likely facilitates the conventional Pd-catalyzed pathway by introducing a radical-generating step. Notably, this dual-metal-mediated method can be readily tuned to afford monohydroxylation products by simply reducing the amount of TBHP. Gram-scale reactions and subsequent derivatizations further confirm the practicality of this method. Since the directing carboxyl group can be easily removed via catalytic or thermal decarboxylation, this Pd/Mo bimetallic catalytic system offers a concise synthetic route to meta-diphenolic compounds, the vital fine chemicals conventionally synthesized via multistep industrial processes.
An activity–resistance trade-off constrains enzyme evolution
The presence of self-resistance genes in antibiotic-producing organisms poses a paradox: How can resistance evolve before the antibiotic exists, and how can an antibiotic producer arise without first evolving resistance? Here, we examine the evolutionary origins of self-resistance to mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). The MPA biosynthetic gene cluster (BGC) includes a resistant IMPDH-B. Homologs of IMPDH-B occur not only in MPA producers but also in many nonproducing fungi, where remnants of the MPA BGC remain detectable. The phylogeny of IMPDH-B is incongruent with the fungal species tree, consistent with multiple horizontal gene transfer events between Aspergillus and Sordariomycetes. We characterized eleven extant IMPDH-Bs, five from MPA producers and six from nonproducers, along with seven resurrected ancestral enzymes (Anc1–Anc7). MPA resistance appeared between Anc2 and Anc3 and coincided with a loss of catalytic efficiency. Across both ancestral and extant enzymes, MPA resistance correlated strongly with reduced activity, revealing a robust activity–resistance trade-off that has persisted for millions of years. Unexpectedly, both the IMPDH-Bs and ancestral enzymes Anc3–Anc7 were also resistant to ribavirin-5′-monophosphate (RVP), an IMP-competitive inhibitor. Because MPA and RVP bind to similar enzyme conformations, the activity–resistance trade-off may reflect a design constraint imposed by the need to maintain resistance to multiple inhibitors. Intriguingly, although Anc1 and Anc2 are equally sensitive to MPA, Anc2 shows reduced susceptibility to RVP. This pattern suggests that preexisting resistance to another IMPDH inhibitor may have created a permissive background for the later evolution of MPA biosynthesis.
Association between ABO and Rh blood groups and subtypes of age-related macular degeneration: A cross-sectional study
Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment and is driven by complex genetic, inflammatory, and vascular mechanisms. ABO and Rh blood group antigens, which are expressed on vascular endothelium and involved in immune and hemostatic pathways, have been implicated in various systemic diseases; however, their potential association with AMD phenotypic variation remains unclear. In this cross-sectional study, 488 patients with clinically confirmed AMD from a tertiary referral center were included. AMD was classified as neovascular AMD (wet AMD) or nonneovascular AMD (dry AMD) based on multimodal imaging and standardized diagnostic criteria. ABO and Rh blood group data were obtained from medical records, and individuals with major known AMD risk factors, including smoking, alcohol consumption, and obesity, were excluded to reduce confounding. Associations between AMD subtypes and ABO blood groups and Rh factor were evaluated using the Pearson chi-square test, and crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. The mean age of participants was 66.9 ± 4.7 years, and 273 patients (55.9%) had neovascular AMD. A statistically significant association was observed between ABO blood group distribution and AMD subtypes (χ² = 8.31, p = 0.040). A higher proportion of patients with neovascular AMD had blood group A, whereas blood group B was relatively more common among patients with nonneovascular AMD. However, individual pairwise crude odds ratio analyses did not demonstrate statistically significant associations for specific ABO blood groups. No association was observed for Rh status. These findings suggest a possible modest association between overall ABO blood group distribution and AMD phenotype; however, the clinical significance of this relationship remains uncertain, particularly in the absence of multivariable adjustment. Larger multicenter studies with comprehensive multivariable analyses are warranted.
Sentinel plants enable quantitative monitoring of bioavailable nitrate in soils and microbial environments
Microbial transformations of nitrogen in soils strongly influence plant nutrition and ecosystem function, yet monitoring these processes remains challenging. Existing approaches rely largely on extraction-based laboratory assays, limiting the ability to track nitrogen dynamics in situ. Here, we engineer “sentinel plants,” genetically encoded plant biosensors that convert nitrate perception into a quantitative signal reporting plant-accessible nitrate. The sensor uses a synthetic nitrate-responsive promoter to drive a ratiometric luciferase reporter, enabling high-dynamic-range measurements. Sentinel plants exhibited a dose-dependent, reversible nitrate response with high specificity over alternative nitrogen sources. In agricultural soils from multiple California field sites, sensor output tracked analytically measured nitrate levels and resolved incremental nitrate amendments, reporting plant-accessible nitrate in complex soil matrices. Beyond environmental sensing, sentinel plants detected microbially generated nitrate in both liquid culture and a model soil. Using this platform, we characterized a minimal three-member microbial consortium that converted atmospheric nitrogen into plant-available nitrate via sequential nitrogen fixation and nitrification. This consortium increased tissue nitrate accumulation and plant fresh weight, demonstrating that sentinel plants can both monitor nitrate availability and characterize microbial communities that enhance plant growth.