ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum.

Intracellular Mg2+ (iMg2+) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major iMg2+ compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases. However, ERMA uniquely combines a P-type ATPase domain and a GMN motif for ERMg2+ uptake. Experiments reveal that a tyrosine residue is crucial for Mg2+ binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg2+ ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca2+ cycling in mouse Erma+/- cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of ERMg2+ uptake in eukaryotes.

From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.

Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments-a covalent and a noncovalent fragment-were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.

Wide Complex Tachycardia Observed During Pregnancy.

This case describes a 39-year-old pregnant woman with intermittent, transient but rapid palpitations, some with momentary lightheadedness.

Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response.

Fight-or-flight responses involve ß-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for ß-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of ß-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel ß-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.

Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.

Some missense gain-of-function mutations in CACNA1C gene, encoding calcium channel CaV1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with currently no clinically-effective therapeutics. Here we report that pharmacological targeting of sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore electrophysiological function in iPSC-derived cardiomyocytes generated from patients with Timothy syndrome and two common forms of long QT syndrome, type 1 (LQTS1) and 2 (LQTS2), caused by missense trafficking mutations in potassium channels. Electrophysiological recordings demonstrate that an FDA-approved cough suppressant, dextromethorphan, can be used as an agonist of SIGMAR1, to shorten the prolonged action potential in Timothy syndrome cardiomyocytes and human cellular models of LQTS1 and LQTS2. When tested in vivo, dextromethorphan also normalized the prolonged QT intervals in Timothy syndrome model mice. Overall, our study demonstrates that SIGMAR1 is a potential therapeutic target for Timothy syndrome and possibly other inherited arrhythmias such as LQTS1 and LQTS2.

Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet.

The response of vital organs to different types of nutrition or diet is a fundamental question in physiology. We examined the cardiac response to 4 weeks of high-fat diet in mice, measuring cardiac metabolites and mRNA. Metabolomics showed dramatic differences after a high-fat diet, including increases in several acyl-carnitine species. The RNA-seq data showed changes consistent with adaptations to use more fatty acid as substrate and an increase in the antioxidant protein catalase. Changes in mRNA were correlated with changes in protein level for several highly responsive genes. We also found significant sex differences in both metabolomics and RNA-seq datasets, both at baseline and after high fat diet. This work reveals the response of a vital organ to dietary intervention at both metabolomic and transcriptomic levels, which is a fundamental question in physiology. This work also reveals significant sex differences in cardiac metabolites and gene expression.

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet.

Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (Mcu), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.

Lymphatic Dissemination and Axillary Web Syndrome in Primary Cutaneous Tuberculosis Secondary to Needlestick Injury.

Cutaneous tuberculosis secondary to skin inoculation of Mycobacterium tuberculosis is uncommon but it can occur in the health care settings. Herein, we report an unusual case of primary cutaneous tuberculosis of the thumb following a needlestick injury. The infection progressed with a necrotic granuloma, lymphatic dysfunction as visualized by near-infrared fluorescence lymphatic imaging, and the development of an axillary web syndrome.

Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic.

Importance: Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc). Objective: To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19. Design, Setting, and Participants: This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline. Exposures: COVID-19, hydroxychloroquine, azithromycin. Main Outcomes and Measures: Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater. Results: A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19. Conclusions and Relevance: In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas: An Observational Study.

[Figure: see text].

Paracardial fat and vitamin A: a mechanism for regulating exercise performance.

Different fat depots have different physiologic functions. In a provocative study published in this issue of the JCI, Petrosino et al. investigate the role of paracardial fat in whole-body metabolism and exercise physiology. Petrosino et al. show that paracardial fat samples from older mice or mice fed a Western diet had decreased levels of alcohol dehydrogenase 1 (ADH1). Paracardial fat samples from humans with obesity also had decreased levels of ADH1 mRNA, supporting the translational relevance. Additional experiments with Adh1-KO mice and surgical fat transplantation experiments provide additional mechanistic insight. Paracardial fat may regulate exercise performance by altering circulating metabolites and/or endocrine effects. ADH1 appears to regulate the mitochondrial content of paracardial fat, a mechanism mediated by retinaldehyde. When ADH1 is active, the paracardial fat has characteristics of brown fat, which is beneficial for exercise performance. Further research is warranted to determine the translational potential of these findings, such as whether removing paracardial fat at the time of open-heart surgery might improve recovery time by increasing exercise capacity.

Frequency of Atrial Arrhythmia in Hospitalized Patients With COVID-19.

There is growing evidence that COVID-19 can cause cardiovascular complications. However, there are limited data on the characteristics and importance of atrial arrhythmia (AA) in patients hospitalized with COVID-19. Data from 1,029 patients diagnosed with of COVID-19 and admitted to Columbia University Medical Center between March 1, 2020 and April 15, 2020 were analyzed. The diagnosis of AA was confirmed by 12 lead electrocardiographic recordings, 24-hour telemetry recordings and implantable device interrogations. Patients' history, biomarkers and hospital course were reviewed. Outcomes that were assessed were intubation, discharge and mortality. Of 1,029 patients reviewed, 82 (8%) were diagnosed with AA in whom 46 (56%) were new-onset AA 16 (20%) recurrent paroxysmal and 20 (24%) were chronic persistent AA. Sixty-five percent of the patients diagnosed with AA (n=53) died. Patients diagnosed with AA had significantly higher mortality compared with those without AA (65% vs 21%; p < 0.001). Predictors of mortality were older age (Odds Ratio (OR)=1.12, [95% Confidence Interval (CI), 1.04 to 1.22]); male gender (OR=6.4 [95% CI, 1.3 to 32]); azithromycin use (OR=13.4 [95% CI, 2.14 to 84]); and higher D-dimer levels (OR=2.8 [95% CI, 1.1 to 7.3]). In conclusion, patients diagnosed with AA had 3.1 times significant increase in mortality rate versus patients without diagnosis of AA in COVID-19 patients. Older age, male gender, azithromycin use and higher baseline D-dimer levels were predictors of mortality.

Degradation of lymphatic anatomy and function in early venous insufficiency.

OBJECTIVE: We used near-infrared fluorescence lymphatic imaging in a pilot study to assess the lymphatics in preulcerative (C2-C4) venous insufficiency and determine whether involvement and/or degradation of lymphatic anatomy or function could play a role in the progression of chronic venous insufficiency. We also explored the role of lymphatics in early peripheral arterial disease. METHODS: After informed consent and intradermal injections of indocyanine green for rapid lymphatic uptake, near-infrared fluorescence lymphatic imaging was used to assess the lymphatic anatomic structure and quantify the lymphatic propulsion rates in subjects with early venous insufficiency. The anatomic observations included interstitial backflow, characterized by the abnormal spreading of indocyanine green from the injection site primarily into the surrounding interstitial tissues; dermal backflow, characterized by the retrograde movement of dye-laden lymph from collecting lymphatics into the lymphatic capillaries; and lymphatic vessel segmentation and dilation. RESULTS: Ten subjects with venous insufficiency were enrolled, resulting in two legs with C2 disease, nine legs with C3 disease, eight legs with C4 disease, and one leg with C5 disease. Interstitial and/or dermal backflow were observed in 25%, 33%, and 41% of the injection sites in each limb with C2, C3, and C4 disease, respectively. Distinct vessel segmentation and dilation were observed in limbs with a C3 and higher classification, and dermal backflow proximal to the injection sites was observed in two legs with C4 disease and in the inguinal region of the C5 study subject. The overall average lymph propulsion rates were 1.3 ± 0.4, 1.2 ± 0.7, and 0.8 ± 0.5 contractile events/min for limbs with C2, C3, and C4 disease, respectively. One subject with peripheral arterial disease, who had previously undergone bypass surgery, presented with extensive dermal backflow and lymphatic reflux. CONCLUSIONS: Near-infrared fluorescence lymphatic imaging demonstrated that, compared with normal health subjects, the lymphatic anatomy and contractile function generally degrade with the severity of venous insufficiency. Lymphatic abnormalities mimic those in early cancer-acquired lymphedema subjects, as previously observed by us and others. Additional studies are needed to decipher the relationship, including any causality, between lymphatic dysfunction and peripheral vascular disease and venous insufficiency.

Admission Cardiac Diagnostic Testing with Electrocardiography and Troponin Measurement Prognosticates Increased 30-Day Mortality in COVID-19.

Background Cardiovascular involvement in coronavirus disease 2019 (COVID-19) is common and leads to worsened mortality. Diagnostic cardiovascular studies may be helpful for resource appropriation and identifying patients at increased risk for death. Methods and Results We analyzed 887 patients (aged 64±17 years) admitted with COVID-19 from March 1 to April 3, 2020 in New York City with 12 lead electrocardiography within 2 days of diagnosis. Demographics, comorbidities, and laboratory testing, including high sensitivity cardiac troponin T (hs-cTnT), were abstracted. At 30 days follow-up, 556 patients (63%) were living without requiring mechanical ventilation, 123 (14%) were living and required mechanical ventilation, and 203 (23%) had expired. Electrocardiography findings included atrial fibrillation or atrial flutter (AF/AFL) in 46 (5%) and ST-T wave changes in 306 (38%). 27 (59%) patients with AF/AFL expired as compared to 181 (21%) of 841 with other non-life-threatening rhythms (P<0.001). Multivariable analysis incorporating age, comorbidities, AF/AFL, QRS abnormalities, and ST-T wave changes, and initial hs-cTnT ≥20 ng/L showed that increased age (HR 1.04/year), elevated hs-cTnT (HR 4.57), AF/AFL (HR 2.07), and a history of coronary artery disease (HR 1.56) and active cancer (HR 1.87) were associated with increased mortality. Conclusions Myocardial injury with hs-cTnT ≥20 ng/L, in addition to cardiac conduction perturbations, especially AF/AFL, upon hospital admission for COVID-19 infection is associated with markedly increased risk for mortality than either diagnostic abnormality alone.

Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.

INTRODUCTION: Electrocardiographic characteristics in COVID-19-related mortality have not yet been reported, particularly in racial/ethnic minorities. METHODS AND RESULTS: We reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus nonarrhythmic death. Of 1258 patients screened, 133 died and were enrolled. Of these, 55.6% (74/133) were male, 69.9% (93/133) were racial/ethnic minorities, and 88.0% (117/133) had cardiovascular disease. The last cardiac rhythm recorded was VT or fibrillation in 5.3% (7/133), pulseless electrical activity in 7.5% (10/133), unspecified bradycardia in 0.8% (1/133), and asystole in 26.3% (35/133). Most 74.4% (99/133) died receiving comfort measures only. The most common abnormalities on admission electrocardiogram included abnormal QRS axis (25.8%), atrial fibrillation/flutter (14.3%), atrial ectopy (12.0%), and right bundle branch block (11.9%). During hospitalization, an additional 17.6% developed atrial ectopy, 14.7% ventricular ectopy, 10.1% atrial fibrillation/flutter, and 7.8% a right ventricular abnormality. Arrhythmic death was confirmed or suspected in 8.3% (11/133) associated with age, coronary artery disease, asthma, vasopressor use, longer admission corrected QT interval, and left bundle branch block (LBBB). CONCLUSIONS: Conduction, rhythm, and electrocardiographic abnormalities were common during COVID-19-related hospitalization. Arrhythmic death was associated with age, coronary artery disease, asthma, longer admission corrected QT interval, LBBB, ventricular ectopy, and usage of vasopressors. Most died receiving comfort measures.

Mechanisms of Chronic Metabolic Stress in Arrhythmias.

Cardiac arrhythmias are responsible for many cardiovascular disease-related deaths worldwide. While arrhythmia pathogenesis is complex, there is increasing evidence for metabolic causes. Obesity, diabetes, and chronically consuming high-fat foods significantly increase the likelihood of developing arrhythmias. Although these correlations are well established, mechanistic explanations connecting a high-fat diet (HFD) to arrhythmogenesis are incomplete, although oxidative stress appears to be critical. This review investigates the metabolic changes that occur in obesity and after HFD. Potential therapies to prevent or treat arrhythmias are discussed, including antioxidants.

The Prognostic Value of Electrocardiogram at Presentation to Emergency Department in Patients With COVID-19.

OBJECTIVE: To study whether combining vital signs and electrocardiogram (ECG) analysis can improve early prognostication. METHODS: This study analyzed 1258 adults with coronavirus disease 2019 who were seen at three hospitals in New York in March and April 2020. Electrocardiograms at presentation to the emergency department were systematically read by electrophysiologists. The primary outcome was a composite of mechanical ventilation or death 48 hours from diagnosis. The prognostic value of ECG abnormalities was assessed in a model adjusted for demographics, comorbidities, and vital signs. RESULTS: At 48 hours, 73 of 1258 patients (5.8%) had died and 174 of 1258 (13.8%) were alive but receiving mechanical ventilation with 277 of 1258 (22.0%) patients dying by 30 days. Early development of respiratory failure was common, with 53% of all intubations occurring within 48 hours of presentation. In a multivariable logistic regression, atrial fibrillation/flutter (odds ratio [OR], 2.5; 95% CI, 1.1 to 6.2), right ventricular strain (OR, 2.7; 95% CI, 1.3 to 6.1), and ST segment abnormalities (OR, 2.4; 95% CI, 1.5 to 3.8) were associated with death or mechanical ventilation at 48 hours. In 108 patients without these ECG abnormalities and with normal respiratory vitals (rate <20 breaths/min and saturation >95%), only 5 (4.6%) died or required mechanical ventilation by 48 hours versus 68 of 216 patients (31.5%) having both ECG and respiratory vital sign abnormalities. CONCLUSION: The combination of abnormal respiratory vital signs and ECG findings of atrial fibrillation/flutter, right ventricular strain, or ST segment abnormalities accurately prognosticates early deterioration in patients with coronavirus disease 2019 and may assist with patient triage.

Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States.

BACKGROUND: The COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking. METHODS: In this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide. RESULTS: Reasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely. CONCLUSION: Our experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.

Fragment-based Differential Targeting of PPI Stabilizer Interfaces.

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.