Browse Articles

Combining Quizartinib with intensive chemotherapy in older patients with newly diagnosed AML: results of the UK NCRI AML18 Trial

We assessed the addition of the tyrosine kinase inhibitor Quizartinib, following intensive chemotherapy and as maintenance, in patients aged >60 years with AML or high-risk MDS, regardless of FLT3 mutation status. 463 patients (median age 68yrs) were randomised (1:1) to receive Quizartinib 40mg or not for 14 days immediately following chemotherapy courses 2 and 3, plus 28 additional days; those allocated Quizartinib were further randomised (1:1) to either 12 additional 28-day maintenance courses (long Quizartinib), or no further treatment (short Quizartinib). Median follow-up was 76 months. 314 patients were FLT3 wild type (WT); 116 had FLT3 mutations. The primary endpoint, overall survival (OS) unselected by FLT3 status, showed no significant difference (HR 0.99, 95% CI 0.79-1.24, p=0.937) and there was an increase in non-relapse mortality with Quizartinib (HR 1.64, 95% CI 1.04-2.59, p=0.032). In a pre-planned subgroup analysis, FLT3-mutated patients who received Quizartinib had significantly improved OS (HR 0.59, 95% CI 0.37-0.93, p=0.024) due to reduced relapse risk (HR 0.57, 95% CI 0.35-0.91, p=0.017) with greater benefit in the short Quizartinib group (HR 0.49, 95% CI 0.24-1.02, p=0.055). In FLT3-WT patients there was no survival benefit and no reduction in relapse risk. No significant differences were seen in time to hematologic count recovery or in the duration of hospitalisation. The most observed grade 3/4 adverse events were febrile neutropenia. In conclusion, the addition of Quizartinib to intensive chemotherapy, delayed until chemotherapy course 2, prolonged OS in older patients with FLT3-mutated AML but did not improve OS in non-FLT3 selected patients. ISRCTN-31682779, EudraCR-2013-002730-21

Bifluorinated Motif‐Tailored Hybrid Membranes for Ultra‐Permeable CO ₂ Separation From Air Under High Humidity

ABSTRACT Membrane‐based direct air capture (m‐DAC) offers an energy‐ efficient route to mitigate rising atmospheric CO 2 , but its practical deployment is hindered by low CO 2 concentration and high humidity. Herein, we propose a “Sailing‐with‐Water” strategy that turns humidity from an obstacle into a mass‐transfer driving force. The bifluorinated motifs are engineered by integrating fluorinated ionic liquid@UiO66 (IL@UiO) as porous fillers and a novel polymer, PIM‐1DFBP, as the second fluorine source. The abundant fluorine sites within the membrane facilitate CO 2 capture and enrichment from dilute streams via Lewis acid–base interactions. Notably, under high humidity conditions, the fluorine sites in the membrane form a hydrogen‐bond network with water molecules, creating a polar microenvironment that further enhances CO 2 affinity and builds ultrafast channels for CO 2 permeation. The optimized membrane achieves a CO 2 permeability of 12697.08 Barrer and CO 2 /N 2 selectivity of 44.06 under 65% relative humidity, surpassing the 2019 Robeson upper bound. The membrane also exhibits 180‐days stability, large‐area defect‐free fabrication, and process simulation shows that only 612.37 m 2 is needed to reach 40% CO 2 outlet concentration. This work provides a humidity‐resistant paradigm for high‐performance m‐DAC.

Lipoprotein(a) in High-Risk Primary Prevention: Making the Best of What We Have

Translational Regulation of Sf1 Integrates Alternative Splicing and Hematopoietic Stem Cell Fate

The transition of hematopoietic stem cells (HSCs) from quiescence to lineage commitment requires precise post-transcriptional control, yet the contribution of mRNA isoform regulation remains poorly defined. Here, we identify a translationally controlled splicing program that contributes to HSC fate decisions. Using activity-based signatures of 305 splicing regulators, we uncover widespread post-transcriptional modulation of the spliceosome in stem and progenitor cells. The branch-point recognition factor Sf1 emerges as a key node, regulated by a conserved structured 5′ UTR that cooperates with the RNA-binding protein Igf2bp2 to control its translation. Disrupting this cis-trans module reduces Sf1 protein synthesis and skews differentiation toward stem and erythroid programs. Mechanistically, Sf1-dependent alternative splicing remodels 5′ UTRs of hematopoietic and DNA damage response genes, altering their translation and modulating DNA damage resolution. Together, these findings reveal an unrecognized translational layer controlling spliceosome activity and link RNA regulons, alternative splicing, and HSC fate determination.

High‐Performance, Activation‐Free Magnesium‐Ion Batteries Enabled by Ionic Liquid Electrolyte Additive

ABSTRACT Magnesium‐ion batteries (MIBs), as a highly promising next‐generation energy storage technology, benefit from the high theoretical volumetric capacity (3833 mAh L −1 ) of magnesium metal and its intrinsic safety. However, its commercialization is still hindered by sluggish de‐solvation kinetics during cycling, which prolongs the activation periods to reach maximum capacity and impairs rate performance. To overcome this bottleneck, we add 4‐ethyl‐4‐methylmorpholinium cation (EMM + ) as an additive into the conventional all‐phenyl‐complex (APC) electrolyte. Density functional theory computations confirm that EMM + shows a strong affinity for chloride ions (−0.513 eV), which weakens the Mg–Cl coordination and, thus promotes Mg 2+ de‐solvation. In CuS‐based MIBs, the modified APC‐EMM electrolyte eliminates the activation cycles that are required with pure APC, and achieves a high specific capacity of 405.1 mAh g −1 at 100 mA g −1 , while maintaining excellent rate performance (220.1 mAh g −1 at 1 A g −1 ). Notably, this electrolyte also shows significant improvements in capacity, activation kinetics, and cycling stability when applied to other cathode materials, including CuSe, Cu 7 Te 4 , Mo 6 S 8 , and perylene‐3,4,9,10‐tetracarboxylic dianhydride. This study establishes a de‐solvation‐accelerated electrolyte design concept as a universal paradigm for the development of high‐performance MIBs.

In Memoriam, Eugene Braunwald, MD: The Gift That Keeps on Giving

A Superhydrophobic Nanotrap Porous Organic Cage for Efficient Capture of SF ₆ Under Dry and Humid Conditions

ABSTRACT Effective SF 6 capture and recovery are essential for reducing greenhouse gas emissions and promoting resource recycling, yet many porous materials exhibit reduced separation performance for SF 6 /N 2 mixtures in humid environments due to water adsorption competition or structural instability. To address this challenge, we propose a “superhydrophobic nanotrap” strategy by designing a nitrogen‐rich superhydrophobic porous organic cage (POC) named IMUPOC‐DA. This material incorporates a moisture‐blocking shield of superhydrophobic isobutyl chains and an inner cavity with a π‐system and Lewis base sites that synergistically enhance SF 6 trapping. At 298 K and 1 bar, IMUPOC‐DA achieves an SF 6 adsorption capacity of 53.6 cm 3 g −1 and an SF 6 /N 2 uptake ratio of 20.02, a record‐high reported thus far for POC‐based adsorbents. More importantly, the superhydrophobic surface endows the material with an extremely low water uptake (72.1 mg g −1 ), a high water contact angle (150.11 ° ), and excellent water stability. Dynamic column breakthrough experiments under 80% relative humidity show nearly unchanged SF 6 breakthrough time compared with dry conditions, demonstrating outstanding SF 6 /N 2 separation performance even in a moist environment. Therefore, this work not only provides a high‐performance candidate for industrial SF 6 recovery but also presents a general design strategy for developing moisture‐resistant adsorbents for gas separation.

Breaking the Anchor: Overcoming Diagnostic Bias in Overlapping Cardiac Pathologies

Chemical Synthesis and Immunological Evaluation of <i>Escherichia coli</i> O29, <i>Shigella dysenteriae</i> Serotype 11, and <i>Proteus vulgaris</i> O12 O‐Antigen Oligosaccharides

ABSTRACT Escherichia coli ( E. coli ), Shigella dysenteriae ( S. dysenteriae ), and Proteus vulgaris ( P. vulgaris ) are the leading bacterial causes of death and diseases in many countries. Vaccines are economical and effective tools against bacterial infection. Herein, we present the first total synthesis and immunological evaluation of the E. coli O29, S. dysenteriae serotype 11, and P. vulgaris O12 O‐antigen decasaccharides, pentasaccharides, and related oligosaccharide fragments. We found that the hexasaccharide, including two repeating units of the core trisaccharide, was the optimal epitope, which was conjugated with the carrier protein CRM197 to furnish a semisynthetic glycoconjugate vaccine. The glycoconjugate vaccine induced a robust antigen‐specific immune response, and the antibody sera could recognize the surface O‐antigens of E. coli O29. This glycoconjugate vaccine, including a common trisaccharide fragment, existed in many bacterial O‐antigens, which can be further used as a potential broad‐spectrum vaccine against E. coli , S. dysenteriae , P. vulgaris , and Cronobacter malonaticus (C. malonaticus) .

Angiotensin Receptor Neprilysin Inhibitor in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Regurgitation: The PRAISE-MR Randomized Trial

BACKGROUND: Atrial functional mitral regurgitation (AFMR) characterizes a high-risk phenotype in heart failure with preserved ejection fraction (HFpEF). Although sacubitril/valsartan reduces functional mitral regurgitation (MR) in HF with reduced EF (HFrEF), its impact on exercise hemodynamics and the dynamic burden of AFMR in HFpEF remains to be elucidated. METHODS: This multicenter, randomized, open-label trial with blinded primary endpoint assessment assigned 84 patients with symptomatic HFpEF and at least moderate AFMR within the previous year to sacubitril/valsartan (n=41) or standard-of-care (SOC; n=43). The primary outcome was the 6-month change in the exercise mean pulmonary arterial pressure to cardiac output (mPAP/CO) slope, assessed using cardiopulmonary exercise testing with simultaneous echocardiography (CPETecho). Secondary outcomes included changes in peak oxygen consumption (peak VO 2 ), Kansas City Cardiomyopathy Questionnaire (KCCQ), N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, left atrial (LA) volume and function, and AFMR severity in rest and during stress. RESULTS: At 6 months, sacubitril/valsartan significantly improved the mPAP/CO slope compared with SOC (adjusted between-group difference in change, –0.93 mm Hg/L/min; 95% CI, –1.80 to –0.07; P =0.035). This hemodynamic benefit was accompanied by improvements in peak VO 2 (mean change, +0.9 versus –0.6mL/kg/min; P =0.002) and KCCQ (median increase, 10 versus 2 points; P =0.002). Significant reductions in NT-proBNP and LA volume were observed ( P &lt;0.001 for both), alongside a significant blunting of the dynamic MR increase during exercise ( P =0.020). Target dose was achieved in 60% of patients, with symptomatic hypotension as the primary titration-limiting factor. CONCLUSIONS: In HFpEF and AFMR, sacubitril/valsartan was associated with improvements in exercise hemodynamics and peak VO 2 , along with attenuation of the exercise-induced increase in AFMR. These findings suggest a phenotype-specific benefit, warranting confirmation in larger, placebo-controlled, clinical outcome trials. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05991284. EudraCT: 2023-506634-70-00

Laroprovstat, the First Oral Small-Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results From a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial in Treatment-Naïve Patients

BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective therapy for reducing low-density lipoprotein (LDL) cholesterol (LDL-C) in adults with hyperlipidemia, including heterozygous familial hypercholesterolemia, thereby lowering cardiovascular risk. Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved. METHODS: Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain. The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human PCSK9 . Safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat were assessed in healthy participants with LDL-C ≥70 and ≤190 mg/dL after single ascending doses. Laroprovstat was also assessed in participants with LDL-C ≥100 and ≤190 mg/dL at doses of 1 mg or 30 mg versus placebo administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period. RESULTS: Laroprovstat does not inhibit the PCSK9–LDL receptor interaction but stabilizes the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor. Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9 . Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (≈40 hours). There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (area under the plasma concentration-time curve inf and C max geometric mean reduction of 1.15 [90% CI, 1.11–1.19] and 1.06 [90% CI, 1.00–1.13], respectively). After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 18%–38%) and 51% (95% CI, 44%–58%) compared with baseline. Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 and 30 mg, respectively. CONCLUSIONS: Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food. In treatment-naïve participants with hypercholesterolemia, combined rosuvastatin 20 mg and laroprovstat 30 mg treatment led to an 80% LDL-C reduction, supporting further development of laroprovstat as the first oral small-molecule PCSK9 inhibitor in patients with hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05384262.

Cobalt‐Catalyzed Radical Ligand Transfer (RLT) Enables <i>Remote</i> ‐Markovnikov Hydroamination of Alkenes

ABSTRACT Amino alcohols are prevalent in pharmaceuticals, agrochemicals, and functional materials, yet regioselective remote C─N bond formation from simple alkenes remains limited. We report a remote ‐Markovnikov formal 1,3‐hydroamination of allyl carboxylates enabled by cooperative photoredox, cobalt, and Brønsted acid catalysis. The reaction proceeds via metal–hydride hydrogen atom transfer (MHAT) followed by 1,2‐radical acyloxy migration (1,2‐RAM) to generate a tertiary carbon‐centered radical at a site remote from the original alkene, affording protected tertiary alkyl amino alcohols across a broad substrate scope, with secondary variants also accessible. Experimental and computational studies support a C─N bond‐forming step best described as radical ligand transfer (RLT) at a Co(III)─N intermediate, rather than Co(IV)/S N 2 or carbocationic pathways. This rare nitrogen‐transfer manifold accounts for the observed regioselectivity and catalyst‐influenced stereochemical outcomes. By enabling migration‐controlled 1,3‐hydroamination, this strategy complements conventional 1,2‐hydroamination and expands accessible amino alcohol chemical space.

A Slow Regular Rhythm After TAVR: A Clinical Reasoning Exercise

Cooperative Redox Catalysis of N ₂ O Decomposition by Short‐Range RhO <i> _x </i> and CeO <i> _x </i> Anchored to Co ₃ O ₄

ABSTRACT Hybrid materials based upon mixed metal oxides provide an effective strategy to boost catalytic performance through redox‐induced interfacial engineering. Herein, we present an efficient catalyst toward N 2 O decomposition containing short‐range ordered RhO x and CeO x species anchored to the Co 3 O 4 spinel. The activity enhancement relative to Co 3 O 4 is non‐additive with respect to the RhO x /Co 3 O 4 and CeO x /Co 3 O 4 interfaces and is uniquely linked to the modulation of the Co and Rh oxidation states at a synergistic Rh–O–Co–O–Ce interface. This ensemble provides increased redox flexibility and facilitated lattice oxygen activation, resulting in markedly enhanced N 2 O decomposition. Kinetic analysis and operando modulated excitation x‐ray absorption spectroscopy (ME‐XAS) provide direct mechanistic evidence that N 2 O decomposition proceeds via a multi‐site, cooperative Mars‐van Krevelen pathway, in which Co 3 O 4 –CeO 2 acts as an oxygen reservoir enabling the redox cycling of RhO x species. This study highlights the ability of mixed metal oxide catalysts to exploit interfacial effects to achieve improved activity in redox‐mediated reactions and offers a rationale for the engineering of metal oxide–metal oxide catalysts guided by operando spectroscopy.

Pulsed Field Ablation Versus Sham to Treat Atrial Fibrillation: The PFA-SHAM Randomized Clinical Trial

BACKGROUND: Catheter ablation for atrial fibrillation (AF) is one of the most common cardiovascular procedures being performed worldwide. Despite the large body of evidence of its effectiveness, with a single exception, prior ablation studies were largely unblinded trials. Accordingly, residual concerns remained about placebo effects, both for AF recurrence and, in particular, on subjective outcomes such as quality of life or anxiety. Here, we compared pulsed field ablation (PFA) with a sham procedure to treat patients with symptomatic AF. METHODS: This prospective, sham-controlled, single-blind, randomized clinical trial with blinded end-point assessment enrolled patients with AF that was highly symptomatic (Atrial Fibrillation Effect on Quality-of-Life score &lt;50). Patients were assigned 1:1 to PFA or a sham procedure. All participants received implantable cardiac monitors for continuous rhythm monitoring during follow-up. The 6-month co–primary outcomes were (1) time to first recurrence of atrial tachyarrhythmia and (2) changes from baseline in Atrial Fibrillation Effect on Quality-of-Life scores compared between groups. Secondary outcomes were AF burden and psychological distress (assessed by the Hospital Anxiety and Depression Scale [HADS]). RESULTS: Patients (n=60) were randomized to PFA or sham. At 6 months, the first co–primary end point of AF recurrence was met in 2 patients (6.7%) who underwent PFA and 25 patients (83.3%) who underwent sham (posterior hazard ratio, 19.6 [95% bayesian credible intervals, 6.7–76.9]; posterior probability of superiority &gt;0.99). For the second co–primary end point, Atrial Fibrillation Effect on Quality-of-Life scores showed greater improvement from baseline with PFA than sham (improved by 43.9+18.1 points versus 11.3+27.9 points; posterior median difference, 32.6 [95% bayesian credible interval, 20.2–44.9]; posterior probability of superiority &gt;0.99). AF burden at 6 months was significantly lower in the PFA than the sham group (0 [0–0] versus 0.43 [0.04–3.47]; between group median difference, −0.39 [95% credible interval, −2.5 to −0.1], posterior probability of superiority &gt;0.99). The Hospital Anxiety and Depression Scale score changed by −4 points (−7.8 to −2.0) with PFA and by −0.5 (−4.5 to 1.0) with sham (group median difference, −3.5 [95% credible interval, −6.0 to −1.0]; posterior probability of superiority &gt;0.99). CONCLUSIONS: In patients with AF, PFA was superior to sham in reducing arrhythmia recurrences and burden and improving quality of life and AF-associated psychological distress. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05717725.

One Block, Two Block, or More? Keep Counting

A Platinum(IV) Metallo‐Stapling Approach to Tumor‐Specific Prodrugs for Targeted Chemo‐Immunometabolic Cancer Therapy

ABSTRACT The clinical utility of classical metallodrugs is limited by insufficient tumor selectivity and systemic toxicity. Platinum‐based chemotherapeutics, while foundational in oncology, exemplify this challenge because of their indiscriminate action on both cancerous and healthy cells, leading to detrimental side effects. Inspired by the versatile coordination chemistry in metalloproteins, we developed a platinum(IV)‐based metallo‐stapling strategy to construct tumor‐specific metalloprodrugs. This approach leverages the Pt(IV) complex dually as a chemotherapeutic agent and a structural staple that conformationally rigidifies an epidermal growth factor receptor (EGFR)‐targeting ligand. The resultant macrocyclic metalloprodrug exhibits precise targeting of EGFR‐overexpressing malignancies, achieving in vivo tumor platinum accumulation 7‐fold higher than the parent Pt(II) complex and 5‐fold greater than its linear counterpart due to superior metabolic stability and efficient receptor‐mediated uptake conferred by the macrocyclic architecture. Upon reaching the tumor microenvironment, the construct undergoes dual‐payload release to liberate platinum drug and the IDO‐1 inhibitor NLG919 analogue (NLG), eliciting a robust immunogenic cell death cascade while simultaneously reversing immunosuppression. Furthermore, a combination with an aPD‐L1 immune checkpoint blockade produces a marked synergistic antitumor response. This work establishes Pt(IV)‐directed metallo‐stapling as a versatile platform for precision cancer therapy, offering a generalizable strategy to chemically engineer a broad range of metalloprodrugs with enhanced tumor selectivity and biosafety.

Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis

BACKGROUND: Cardiac sarcoidosis (CS) is an enigmatic disorder characterized by unexplained patchy, sterile granulomas intermixed with preserved myocardium and fibrotic regions without granuloma. CS causes arrhythmias, sudden cardiac death, and heart failure. The mechanisms producing this remarkable histopathology and disease progression remain unexplained. METHODS: Using comprehensive single-cell and spatial transcriptomic analyses, we characterized the cellular composition and gene expression in preserved, granulomatous, and fibrotic regions of human CS hearts. From unexpectedly identified clonally expanded cardiac B cells with rearranged immunoglobulin sequences, we reconstructed antibodies and screened libraries comprising the human peptidome or microbial and allergen peptides to define reactive epitopes in CS hearts. RESULTS: Cellular composition and gene expression differed substantially in CS tissues with preserved, granulomatous, or fibrotic histopathology. Cardiomyocytes upregulated arrhythmogenic and inflammasome transcripts associated with pyroptosis. Cardiomyocytes and fibroblasts activated chemoattractant cytokines that sustained myeloid and lymphoid infiltration. Granulomas contained abundant macrophages expressing modulators of cell–cell fusion, along with Th17-skewed T cells that upregulated B-cell–activating factor, thereby promoting antibody production. Fibrotic regions, without active granulomas, exhibited tertiary lymphoid structures, with clonal expansion of mature B and plasma cells. Reconstructed antibodies derived from expanded B-cell clones were inert to microbial and allergen peptides, but reacted to PPL (periplakin), a desmosome protein, and other peptides expressed on cardiac cells. CONCLUSIONS: Progressive inflammatory signals in CS are mediated by chemoattractant genes in cardiomyocytes and fibroblasts within preserved myocardium, cell–cell fusion modulators in activated macrophages within granulomatous regions, and tertiary lymphoid structures in fibrotic regions that produce patient-specific autoimmune antibodies. Identification of PPL as a CS autoantigen may account for shared clinical manifestations in CS and arrhythmic desmosomal cardiomyopathies. CS autoantigens may underlie enigmatic histopathologic findings, perpetuate disease, and contribute to adverse outcomes. Uncovering an intracardiac humoral autoimmune axis in CS provides specific therapeutic opportunities to limit granuloma formation and B-cell activation, which may reduce arrhythmogenicity and progressive dysfunction. Parallel analytic strategies have potential to define autoantigens in other enigmatic cardiac immune disorders.

Observational Comparative Research in Cardiovascular and Brain Health and Disease: A Scientific Statement From the American Heart Association

Resources for observational comparative research have expanded enormously in recent years to include very large sources of granular, routinely collected health care data and modern statistical, epidemiologic, and econometric techniques. This scientific statement provides an overview of best practices and analytic considerations in observational comparative studies from the perspective of investigators, sponsors, publishers, and consumers of observational research. Observational comparative research is a component of the research landscape that fulfills a role distinct from that of interventional studies in the evaluation of drugs, surgical procedures, medical devices, and health policies. Sources of systematic error (ie, bias) in observational comparative studies include selection bias, information bias, and confounding. Principles from statistical science and econometrics can potentially be used to make causal conclusions from observational data. Target trial emulation is a useful framework to guide the rational design and illuminate the limitations of observational studies. As with interventional research, a formal study protocol should be prepared before every observational study to enhance rigor, reduce data manipulation, and promote transparency of study reporting. Selection of the study data source is a key decision early in the design stage of a study, and should be chosen on the basis of concordance between the needs of the specific study question and the properties of the data set. We recommend the use of causal directed acyclic graphs to clearly specify the study exposure, end points, confounders, colliders, moderators, and mediators. Taken together, these recommendations promote rational design choices and cautious interpretation of the results of observational comparative studies.

Photo‐Triggered, Fast, and Fluorogenic Thiophene‐Based Cycloalkynes for the Bioorthogonal Fluorescent Labeling of 1,3‐Dipole‐Tagged Molecules in No‐Wash Conditions

ABSTRACT Bioorthogonal reactions have revolutionized our way of performing chemistry in a highly complex biological environment. In particular, strain‐promoted 1,3‐dipolar cycloadditions, employing cyclooctyne probes in conjunction with azido‐reporters (strain‐promoted alkyne‐azide cycloaddition, SPAAC), have permitted the labeling and visualization of bio‐macromolecules in vitro, in living cells, as well as in animals. However, SPAAC's slow kinetics (&lt; 1 M −1 s −1 ), in combination with the necessity to eliminate the excess of the used fluorescent probes, have hampered its widespread application, especially for the real‐time imaging of low concentration targets. Here we describe two novel thiophene‐based cycloalkynes that not only exhibit very high kinetics toward a variety of 1,3‐dipoles (up to 1528 M −1 s −1 ), but are also efficiently turned‐on (up to 150‐fold increase in brightness) upon reaction with their target. We demonstrated their fast and fluorogenic capabilities by monitoring the labeling overtime of a glycoprotein in physiological and no‐wash conditions, using as little as 5 µM of the probes and reaching full labeling in less than 15 min. These fluorogenic cycloalkynes significantly expand our chemical biology toolbox, and we anticipate them to open new avenues for the fast and real‐time imaging of biomolecules in complex environments.