Remotely sensing potential climate change tipping points across scales.

Potential climate tipping points pose a growing risk for societies, and policy is calling for improved anticipation of them. Satellite remote sensing can play a unique role in identifying and anticipating tipping phenomena across scales. Where satellite records are too short for temporal early warning of tipping points, complementary spatial indicators can leverage the exceptional spatial-temporal coverage of remotely sensed data to detect changing resilience of vulnerable systems. Combining Earth observation with Earth system models can improve process-based understanding of tipping points, their interactions, and potential tipping cascades. Such fine-resolution sensing can support climate tipping point risk management across scales.

Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts.

Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate that polyamines featuring at least one secondary 1,2-diamine fragment in combination with aromatic units form covalent DNA adducts upon reaction with AP sites (with concomitant cleavage of the AP strand), fU and, to a lesser extent, fC residues. Using small-molecule mimics of AP site and fU, we show that reaction of secondary 1,2-diamines with AP sites leads to the formation of unprecedented 3'-tetrahydrofuro[2,3,4-ef]-1,4-diazepane ('ribodiazepane') scaffold, whereas the reaction with fU produces cationic 2,3-dihydro-1,4-diazepinium adducts via uracil ring opening. The reactivity of polyamines towards AP sites versus fU and fC can be tuned by modulating their chemical structure and pH of the reaction medium, enabling up to 20-fold chemoselectivity for AP sites with respect to fU and fC. This reaction is efficient in near-physiological conditions at low-micromolar concentration of polyamines and tolerant to the presence of a large excess of unmodified DNA. Remarkably, 3'-ribodiazepane adducts are chemically stable and resistant to the action of apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphoesterase 1 (TDP1), two DNA repair enzymes known to cleanse a variety of 3' end-blocking DNA lesions.

Idiopathic ventricular fibrillation associated with long-coupled Purkinje ectopy.

INTRODUCTION: Idiopathic ventricular fibrillation (IVF) is mainly associated with and triggered by short-coupled (R-on-T) ventricular ectopics. However, little is known about the risk of VF associated with long-coupled premature ventricular complexes (LCPVCs). OBJECTIVE: To examine the prevalence and characteristics of IVF patients presenting with LCPVCs. METHODS: Consecutive patients with IVF and PVCs from five arrhythmia referral centers were reviewed. We included patients presenting LCPVCs, defined as PVCs falling after the end of the T wave, with a normal QTc interval. We evaluated demographics, medical history, and clinical circumstances associated with PVCs and VF episodes. The origin of PVCs was determined by invasive mapping. RESULTS: Seventy-nine patients with IVF were reviewed. Among them, 12 (15.2%) met the inclusion criteria (8 women, age 36 ± 14 years). Eleven patients had documented LCPVCs initiating repetitive PVCs or sustained VF, whereas 1 had only documented isolated PVCs. In 10 of 12 patients, PVCs were recorded showing both long and short coupling intervals of 418 ± 46 and 304 ± 33 ms, respectively. Mapping showed that PVCs originated from the left Purkinje in 10 patients, from the right Purkinje in 1 patient, and both in 1 patient. Compared to other patients from the initial cohort, IVF with LCPVCs was associated with a left-sided origin of PVCs (92% in long-coupled IVF vs. 46% of left Purkinje PVCs in short-coupled IVF, p = .004). CONCLUSION: Long-coupled fascicular PVCs, traditionally recognized as benign, can be associated with IVF in a subset of patients. They can induce IVF by themselves or in association with short-coupled PVCs.

Malignant Purkinje ectopy induced by sodium channel blockers.

BACKGROUND: Sodium channel blocker (SCB) infusion is used to unmask the electrocardiographic pattern of Brugada syndrome. The test may also induce premature ventricular complexes (PVCs) in individuals without Brugada pattern, the clinical relevance of which is little known. OBJECTIVE: The purpose of this study was to describe the prevalence of short-coupled (Sc) PVCs induced by ajmaline or flecainide in patients with suspected or documented severe ventricular arrhythmias. METHODS: We reviewed the SCB tests performed in 335 patients with suspected ventricular arrhythmias and structurally normal hearts in 9 centers. ScPVCs were defined as frequent and repetitive PVCs with an R-on-T pattern on SCB tests. Repeated SCB tests were performed in 7 patients and electrophysiological mapping of ScPVCs in 9. RESULTS: Sixteen patients (8 men; mean age 36 ± 11 years) showed ScPVCs and were included. ScPVCs appeared 229 ± 118 seconds after the initiation of infusion and displayed coupling intervals of 288 ± 28 ms. ScPVC patterns were monomorphic in 12 patients, originating from the Purkinje system in mapped patients. Repetitive PVCs were induced in 15 patients (94%) including polymorphic ventricular tachycardias in 9 (56%). SCB infusion was repeated 45 (interquartile range 0.6-46) months later and induced identical ScPVC in all. SCB test was the only mean to reveal the malignant arrhythmia in 6 patients. Catheter ablation was performed in 9 patients, resulting in arrhythmia elimination in 8 with a follow-up of 6 (interquartile range 2-9) years. CONCLUSION: SCB can induce ScPVC, mostly from Purkinje tissue, in a small subset of patients with idiopathic ventricular arrhythmias. Its high reproducibility suggests a distinct individual mechanism.

Assessment of presumed small-molecule ligands of telomeric i-DNA by biolayer interferometry (BLI).

Biolayer interferometry (BLI) and circular dichroism (CD) spectroscopy were used to investigate the interaction between previously reported i-motif DNA (i-DNA) ligands and folded or unfolded i-DNA in acidic (pH 5.5) and near-neutral (pH 6.5) conditions. We observed that although several ligands, in particular macrocyclic bis-acridine (BisA) and pyridostatin (PDS), showed good affinities for the telomeric i-motif forming sequence, none of the ligands displayed selective interactions with the i-DNA structure nor was able to promote its formation.

Catheter ablation in adults with congenital heart disease: A 15-year perspective from a tertiary centre.

BACKGROUND: With the growing adult congenital heart disease (ACHD) population, the number of catheter ablation procedures is expected to dramatically increase. Data reporting experience and evolution of catheter ablation in patients with ACHD, over a significant period of time, remain scarce. AIM: We aimed to describe temporal trends in volume and outcomes of catheter ablation in patients with ACHD. METHODS: This was a retrospective observational study including all consecutive patients with ACHD undergoing attempted catheter ablation in a large tertiary referral centre over a 15-year period. Acute procedural success rate and freedom from recurrence at 12 and 24 months were analysed. RESULTS: From November 2004 to November 2019, 302 catheter ablations were performed in 221 patients with ACHD (mean age 43.6±15.0 years; 58.9% male sex). The annual number of catheter ablations increased progressively from four to 60 cases per year (P<0.001). Intra-atrial reentrant tachycardia/focal atrial tachycardia was the most common arrhythmia (n=217, 71.9%). Over the study period, acute procedural success rate increased from 45.0% to 93.4% (P<0.001). Use of irrigated catheters (odds ratio [OR] 4.03, 95% confidence interval [CI] 1.86-8.55), a three-dimensional mapping system (OR 3.70, 95% CI 1.72-7.74), contact force catheters (OR 3.60, 95% CI 1.81-7.38) and high-density mapping (OR 3.69, 95% CI 1.82-8.14) were associated with acute procedural success. The rate of freedom from any recurrence at 12 months increased from 29.4% to 66.2% (P=0.001). Seven (2.3%) non-fatal complications occurred. CONCLUSIONS: The number of catheter ablation procedures in patients with ACHD has increased considerably over the past 15 years. Growing experience and advances in ablative technologies appear to be associated with a significant improvement in acute and mid-term outcomes.

Access to a stabilized i-motif DNA structure through four successive ligation reactions on a cyclopeptide scaffold.

i-Motifs are largely underexplored tetraplex nucleic acid structures which have been suggested to perform essential biological functions and might constitute future therapeutic targets. i-Motifs generally require acidic conditions to fold in vitro, a particularity which significantly complicates the use of native i-motif forming sequences for interaction studies with potential ligands and biological components (e.g. proteins). In this context, we report herein on the assembly of a peptide-DNA conjugate capable of folding at room temperature into a stable i-motif structure at neutral pH. To achieve the controlled assembly of the i-motif forming conjugate, we developed a new synthetic pathway of four successive orthogonal ligation reactions between bifunctional C-rich DNA strands and a tetrafunctional cyclopeptide scaffold.

Radiotherapy in Patients With a Cardiac Implantable Electronic Device.

Recently, the Heart Rhythm Society published recommendations on management of patients with cardiac implantable electronic device (CIED) who require radiotherapy (RT). We aimed to report the experience of a teaching hospital, and discuss our practice in the context of recently published guidelines. We identified all consecutive CIED recipients (12,736 patients) who underwent RT between March 2006 and June 2017. Among them, 90 (1%) patients (78.2 ± 10 years, 73% male) had a CIED: 82 pacemakers and 8 implantable cardioverter-defibrillators. Two patients required CIED extraction prior to RT for ipsilateral breast cancer (no device replacement in 1 patient). Four patients (5%) were considered at high-risk, 35 (39%) at intermediate-risk, and the remaining 50 (56%) at low-risk for CIED dysfunction. Overall, only a minority of patients followed recommended local protocol during RT delivery (31%) and during follow-up (56%). CIED malfunction was detected in 5 patients (6%), mainly back-up mode resetting (80%), with 4 (including 3 pelvic cancer location) patients initially classified as being at intermediate-risk and 1 at low-risk. Four out of the 5 patients with CEID malfunction had received neutron producing beams. In conclusion, our findings underline the lack of rigorous monitoring of patients undergoing RT (though CIED malfunction appears to be rare and relatively benign in nature), and emphasize the interest of considering neutron producing beam for risk stratification as recommended in recent guidelines. Optimization of patient's management requires a close collaboration between both CIED clinicians and radiation oncologists, and more systematic remote CIED monitoring may be helpful.

Idiopathic Ventricular Fibrillation: Role of Purkinje System and Microstructural Myocardial Abnormalities.

Idiopathic ventricular fibrillation is diagnosed in patients who survived a ventricular fibrillation episode without any identifiable structural or electrical cause after extensive investigations. It is a common cause of sudden death in young adults. The study reviews the diagnostic value of systematic investigations and the new insights provided by detailed electrophysiological mapping. Recent studies have shown the high incidence of microstructural cardiomyopathic areas, which act as the substrate of ventricular fibrillation re-entries. These subclinical alterations require high-density endo- and epicardial mapping to be identified using electrogram criteria. Small areas are involved and located individually in various sites (mostly epicardial). Their characteristics suggest a variety of genetic or acquired pathological processes affecting cellular connectivity or tissue structure, such as cardiomyopathies, myocarditis, or fatty infiltration. Purkinje abnormalities manifesting as triggering ectopy or providing a substrate for re-entry represent a second important cause. The documentation of ephemeral Purkinje ectopy requires continuous electrocardiography monitoring for diagnosis. A variety of diseases affecting Purkinje cell function or conduction are potentially at play in their pathogenesis. Comprehensive investigations can therefore allow the great majority of idiopathic ventricular fibrillation to ultimately receive diagnoses of a cardiac disease, likely underlain by a mosaic of pathologies. Precise phenotypic characterization has significant implications for interpretation of genetic variants, the risk assessment, and individual therapy. Future improvements in imaging or electrophysiological methods may hopefully allow the identification of the subjects at risk and the development of primary prevention strategies.

Catheter ablation of intra-atrial reentrant/focal atrial tachycardia in adult congenital heart disease: Value of final programmed atrial stimulation.

BACKGROUND: While outcomes of intra-atrial reentrant/focal atrial tachycardia (IART/FAT) catheter ablation have considerably improved in adult congenital heart disease (ACHD), recurrences remain common with different circuits frequently encountered. OBJECTIVE: We aimed to assess the value of programmed atrial stimulation after successful clinical IART/FAT catheter ablation in patients with ACHD. METHODS: This is a retrospective study including all patients with ACHD undergoing IART/FAT catheter ablation in a tertiary center. After successful catheter ablation of clinical arrhythmia, survival free from arrhythmia recurrence was analyzed according to whether all inducible IARTs/FATs were targeted. RESULTS: From 2004 to 2020, 238 IART/FAT catheter ablation procedures were performed (mean age 44.1 ± 15.0 years; 61.3% men). Acute procedural success of clinical arrhythmia was achieved in 208 procedures (87.4%). Among 122 procedures with programmed atrial stimulation (58.7%), at least 1 other IART/FAT was induced in 61 patients (50%). All inducible IARTs/FATs were ablated in 54 patients (88.5%), whereas 7 patients (11.5%) presented with at least 1 nontargeted inducible IART/FAT. Patients with nontargeted inducible IART/FAT had a higher risk of atrial arrhythmia episodes than did inducible patients treated with ablation of all IARTs/FATs (hazard ratio 5.7; 95% confidence interval 1.7-18.4; P = .004), with 12-month atrial arrhythmias recurrence rates of 22.9% and 77.7%, respectively. Inducible patients with successful ablation of all IARTs/FATs had a risk of recurrence similar to that of noninducible patients (hazard ratio 0.6; 95% confidence interval 0.3-1.3; P = .215). CONCLUSION: Beyond clinical IART/FAT catheter ablation in patients with ACHD, our findings suggest the interest of systematically targeting all remaining inducible arrhythmias, irrespective of whether previously documented.

The Spectrum of Idiopathic Ventricular Fibrillation and J-Wave Syndromes: Novel Mapping Insights.

Idiopathic ventricular fibrillation and J-wave syndromes are causes of sudden cardiac death (SCD) without any identified structural cardiac disease after extensive investigations. Recent data show that high-density electrophysiological mapping may ultimately offer diagnoses of subclinical diseases in most patients including those termed "unexplained" SCD. Three major conditions can underlie the occurrence of SCD: (1) localized depolarization abnormalities (due to microstructural myocardial alteration), (2) Purkinje abnormalities manifesting as triggering ectopy and inducible reentry; or (3) repolarization heterogeneities. Each condition may result from a spectrum of pathophysiologic processes with implications for individual therapy.

Scaffold stabilization of a G-triplex and study of its interactions with G-quadruplex targeting ligands.

G-triplex nucleic acid structures (G3) have been conjectured to form in vivo but little is known about their physiological functions. The identification of ligands capable of specific binding to G3 structures is therefore highly appealing but remains elusive. Here we report on the assembly of a DNA conjugate which folds into a stable G3 structure. The structural mimic was used to probe the interactions between a G3 ligand and first-in-class G4 ligands, revealing signification binding promiscuity.

Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation.

Aims: Recent studies have shown that in more than half of apparently unexplained sudden cardiac arrests (SCA), a specific aetiology can be unmasked by a careful evaluation. The characteristics and the extent to which such cases undergo a systematic thorough investigation in real-life practice are unknown. Methods and results: Data were analysed from an ongoing study, collecting all cases of out-of-hospital cardiac arrest in Paris area. Investigations performed during the index hospitalization or planned after discharge were gathered to evaluate the completeness of assessment of unexplained SCA. Between 2011 and 2016, among the 18 622 out-of-hospital cardiac arrests, 717 survivors (at hospital discharge) fulfilled the definition of cardiac SCA. Of those, 88 (12.3%) remained unexplained after electrocardiogram, echocardiography, and coronary angiography. Cardiac magnetic resonance imaging yielded the diagnosis in 25 (3.5%) cases, other investigations accounted for 14 (2.4%) additional diagnoses, and 49 (6.8%) patients were labelled as idiopathic ventricular fibrillation (IVF) (48.7 ± 15 years, 69.4% male). Among those labelled IVF, only 8 (16.3%) cases benefited from a complete workup (including pharmacological testing). Younger patients [odds ratio (OR) 6.00, 95% confidence interval (CI) 1.80-22.26] and those admitted to university centres (OR 3.60, 95% CI 1.12-12.45) were more thoroughly investigated. Genetic testing and family screening were initiated in only 9 (18.4%) and 12 (24.5%) cases, respectively. Conclusion: Our findings suggest that complete investigations are carried out in a very low proportion of unexplained SCA. Standardized, systematic approaches need to be implemented to ensure that opportunities for specific therapies and preventive strategies (including relatives) are not missed.

New Ruthenium-Based Probes for Selective G-Quadruplex Targeting.

Telomeric regions containing G-quadruplex (G4) structures play a pivotal role in the development of cancers. The development of specific binders for G4s is thus of great interest in order to gain a deeper understanding of the role of these structures, and to ultimately develop new anticancer drug candidates. For several years, RuII complexes have been studied as efficient probes for DNA. Interest in these complexes stems mainly from the tunability of their structures and properties, and the possibility of using light excitation as a tool to probe their environment or to selectively trigger their reaction with a biological target. Herein, we report on the synthesis and thorough study of new RuII complexes based on a novel dipyrazino[2,3-a:2',3'-h]phenazine ligand (dph), obtained through a Chichibabin-like reaction. Luminescence experiments, surface plasmon resonance (SPR), and computational studies have demonstrated that these complexes behave as selective probes for G-quadruplex structures.

Template-Mediated Stabilization of a DNA G-Quadruplex formed in the HIV-1 Promoter and Comparative Binding Studies.

G-rich DNA oligonucleotides derived from the promoter region of the HIV-1 long terminal repeat (LTR) were assembled onto an addressable cyclopeptide platform through sequential oxime ligation, a thiol-iodoacetamide SN2 reaction, and copper-catalyzed azide-alkyne cycloaddition reactions. The resulting conjugate was shown to fold into a highly stable antiparallel G4 architecture as demonstrated by UV, circular dichroism (CD), and NMR spectroscopic analysis. The binding affinities of six state-of-the-art G4-binding ligands toward the HIV-G4 structure were compared to those obtained with a telomeric G4 structure and a hairpin structure. Surface plasmon resonance binding analysis provides new insights into the binding mode of broadly exploited G4 chemical probes and further suggests that potent and selective recognition of viral G4 structures of functional significance might be achieved.

A semisynthetic organism engineered for the stable expansion of the genetic alphabet.

All natural organisms store genetic information in a four-letter, two-base-pair genetic alphabet. The expansion of the genetic alphabet with two synthetic unnatural nucleotides that selectively pair to form an unnatural base pair (UBP) would increase the information storage potential of DNA, and semisynthetic organisms (SSOs) that stably harbor this expanded alphabet would thereby have the potential to store and retrieve increased information. Toward this goal, we previously reported that Escherichia coli grown in the presence of the unnatural nucleoside triphosphates dNaMTP and d5SICSTP, and provided with the means to import them via expression of a plasmid-borne nucleoside triphosphate transporter, replicates DNA containing a single dNaM-d5SICS UBP. Although this represented an important proof-of-concept, the nascent SSO grew poorly and, more problematically, required growth under controlled conditions and even then was unable to indefinitely store the unnatural information, which is clearly a prerequisite for true semisynthetic life. Here, to fortify and vivify the nascent SSO, we engineered the transporter, used a more chemically optimized UBP, and harnessed the power of the bacterial immune response by using Cas9 to eliminate DNA that had lost the UBP. The optimized SSO grows robustly, constitutively imports the unnatural triphosphates, and is able to indefinitely retain multiple UBPs in virtually any sequence context. This SSO is thus a form of life that can stably store genetic information using a six-letter, three-base-pair alphabet.