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Lipid membranes in cells are fluid structures that undergo constant synthesis, remodeling, fission, and fusion. The dynamic nature of lipid membranes enables their use as adaptive compartments, making them indispensable for all life on Earth. Efforts to create life-like artificial cells will likely involve mimicking the structure and function of lipid membranes to recapitulate fundamental cellular processes such as growth and division. As such, there is considerable interest in chemistry that mimics the functional properties of membranes, with the express intent of recapitulating biological phenomena. We suggest expanding the definition of membrane mimetic chemistry to capture these efforts. In this Perspective, we discuss how membrane mimetic chemistry serves the development of artificial cells. By leveraging recent advances in chemical biology and systems chemistry, we have an opportunity to use simplified chemical and biochemical systems to mimic the remarkable properties of living membranes.

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells downregulate glycolytic mechanisms. Metabolic shifts associated with silencing mito-respiratory genes can be detected in vivo with metabolic imaging. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors. Citation Format: Neal K. Bennett, Hiroki J. Nakaoka, Danny Laurent, Ross Okimoto, Yoshitaka Sei, Andrew E. Horvai, Trever G. Bivona, Georgios Batsios, Pavithra Viswanath, Johanna ten Hoeve, Thomas G. Graeber, Ken Nakamura, Jean L. Nakamura. Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1161.

Background Data on the management of Micra transcatheter pacing system (TPS) at the time of an upgrade or during battery depletion is limited. Objective We sought to evaluate the management patterns of patients implanted with a Micra TPS during long-term follow-up. Methods We retrospectively identified patients who underwent Micra implantation from April 2014 to November 2019. We identified patients who underwent extraction (n = 11) or had an abandoned Micra (n = 12). Results We identified 302 patients who received a Micra during the period of the study. Mean age was 72.7 ± 15.4 years, 54.6% were men, and left ventricular ejection fraction was 51.9 ± 5.2%. Mean follow-up was 1105.5 ± 529.3 days. Procedural complications included pericardial tamponade (n = 1) treated with pericardiocentesis, significant rise in thresholds (n = 6) treated with reimplantation (n = 4), and major groin complications (n = 2). Indications for extraction included an upgrade to cardiac resynchronization therapy (CRT) device (n = 3), bridging after extraction of an infected transvenous system (n = 3), elevated thresholds (n = 3), and non-Micra-related bacteremia (n = 2). The median time from implantation to extraction was 78 days (interquartile range: 14-113 days), with the longest extraction occurring at 1442 days. All extractions were successful, with no procedural or long-term complications. Indications for abandonment included the need for CRT (n = 6), battery depletion (n = 2), increasing thresholds/failure to capture (n = 3), and pacemaker syndrome (n = 1). All procedures were successful, with no procedural or long-term complications. Conclusion In this large single-center study, 6% of patients implanted with a Micra required a system modification during long-term follow-up, most commonly due to the requirement for CRT pacing. These patients were managed successfully with extraction or abandonment.

BACKGROUND: Surgical ablation for atrial fibrillation (AF) can be effective, yet has mixed results. It is unclear which endocardial lesions delivered as part of hybrid therapy‚ will best augment surgical lesion sets in individual patients. We addressed this question by systematically mapping AF endocardially after surgical ablation and relating findings to early recurrence, then performing tailored endocardial ablation as part of hybrid therapy. METHODS: We studied 81 consecutive patients undergoing epicardial surgical ablation (stage 1 hybrid), of whom 64 proceeded to endocardial catheter mapping and ablation (stage 2). Stage 2 comprised high-density mapping of pulmonary vein (PV) or posterior wall (PW) reconnections, low-voltage zones (LVZs), and potential localized AF drivers. We related findings to postsurgical recurrence of AF. RESULTS: Mapping at stage 2 revealed PW isolation reconnection in 59.4%, PV isolation reconnection in 28.1%, and LVZ in 42.2% of patients. Postsurgical recurrence of AF occurred in 36 patients (56.3%), particularly those with long-standing persistent AF ( P =0.017), but had no relationship to reconnection of PVs ( P =0.53) or PW isolation ( P =0.75) when compared with those without postsurgical recurrence of AF. LVZs were more common in patients with postsurgical recurrence of AF ( P =0.002), long-standing persistent AF ( P =0.002), advanced age ( P =0.03), and elevated CHA 2 DS 2 -VASc ( P =0.046). AF mapping revealed 4.4±2.7 localized focal/rotational sites near and also remote from PV or PW reconnection. After ablation at patient-specific targets, arrhythmia freedom at 1 year was 81.0% including and 73.0% excluding previously ineffective antiarrhythmic medications. CONCLUSIONS: After surgical ablation, AF may recur by several modes particularly related to localized mechanisms near low voltage zones, recovery of posterior wall or pulmonary vein isolation, or other sustaining mechanisms. LVZs are more common in patients at high clinical risk for recurrence. Patient-specific targeting of these mechanisms yields excellent long-term outcomes from hybrid ablation.

Cardiomyopathies are a heterogeneous collection of diseases that have in common primary functional and structural abnormalities of the heart muscle, often genetically determined. The most effective categorization of cardiomyopathies is based on the presenting phenotype, with hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathy as the prototypes. Sex modulates the prevalence, morpho‐functional manifestations and clinical course of cardiomyopathies. Aspects as diverse as ion channel expression and left ventricular remodeling differ in male and female patients with myocardial disease, although the reasons for this are poorly understood. Moreover, clinical differences may also result from complex societal/environmental discrepancies between sexes that may disadvantage women. This review provides a state‐of‐the‐art appraisal of the influence of sex on cardiomyopathies, highlighting the many gaps in knowledge and open research questions.

Background We aimed to assess the association between number of pregnancies and long‐term progression of cardiac dysfunction, arrhythmias, and event‐free survival in women with pathogenic or likely pathogenic variants of gene encoding for Lamin A/C proteins ( LMNA+). Methods and Results We retrospectively included consecutive women with LMNA+ and recorded pregnancy data. We collected echocardiographic data, occurrence of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, and implantation of cardiac electronic devices (implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator). We analyzed retrospectively complications during pregnancy and the peripartum period. We included 89 women with LMNA+ (28% probands, age 41±16 years), of which 60 had experienced pregnancy. Follow‐up time was 5 [interquartile range, 3–9] years. We analyzed 452 repeated echocardiographic examinations. Number of pregnancies was not associated with increased long‐term risk of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, or implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator implantation. Women with previous pregnancy and nulliparous women had a similar annual deterioration of left ventricular ejection fraction (−0.5/year versus −0.3/year, P =0.37) and similar increase of left ventricular end‐diastolic diameter (0.1/year versus 0.2/year, P =0.09). Number of pregnancies did not decrease survival free from death, left ventricular assist device, or need for cardiac transplantation. Arrhythmias occurred during 9% of pregnancies. No increase in maternal and fetal complications was observed. Conclusions In our cohort of women with LMNA+, pregnancy did not seem associated with long‐term adverse disease progression or event‐free survival. Likewise, women with LMNA+ generally well‐tolerated pregnancy, with a small proportion of patients experiencing arrhythmias.

Chemical cross-linking enables rapid identification of RNA-protein and RNA-nucleic acid inter- and intramolecular interactions. However, no method exists to site-specifically and covalently cross-link two user-defined sites within an RNA. Here, we develop RNA-CLAMP, which enables site-specific and enzymatic cross-linking (clamping) of two selected guanine residues within an RNA. Intramolecular clamping can disrupt normal RNA function, whereas subsequent photocleavage of the cross-linker restores activity. We used RNA-CLAMP to clamp two stem loops within the single-guide RNA (sgRNA) of the CRISPR-Cas9 gene editing system via a photocleavable cross-linker, completely inhibiting gene editing. Visible light irradiation cleaved the cross-linker and restored gene editing with high spatiotemporal resolution. Design of two photocleavable linkers responsive to different wavelengths of light allowed multiplexed photoactivation of gene editing in mammalian cells. This photoactivated CRISPR-Cas9 gene editing platform benefits from undetectable background activity, provides a choice of activation wavelengths, and has multiplexing capabilities.