Harnessing the plant microbiome for sustainable crop production.

Global research on the plant microbiome has enhanced our understanding of the complex interactions between plants and microorganisms. The structure and functions of plant-associated microorganisms, as well as the genetic, biochemical, physical and metabolic factors that influence the beneficial traits of plant microbiota have also been intensively studied. Harnessing the plant microbiome has led to the development of various microbial applications to improve crop productivity in the face of a range of challenges, for example, climate change, abiotic and biotic stresses, and declining soil properties. Microorganisms, particularly nitrogen-fixing rhizobia as well as mycorrhizae and biocontrol agents, have been applied for decades to improve plant nutrition and health. Still, there are limitations regarding efficacy and consistency under field conditions. Also, the wealth of expanding knowledge on microbiome diversity, functions and interactions represents a huge source of information to exploit for new types of application. In this Review, we explore plant microbiome functions, mechanisms, assembly and types of interaction, and discuss current applications and their pitfalls. Furthermore, we elaborate on how the latest findings in plant microbiome research may lead to the development of new or more advanced applications. Finally, we discuss research gaps to fully leverage microbiome functions for sustainable plant production.

Diagnostic reliability of monitoring for premature atrial and ventricular complexes.

AIMS: Short-term ambulatory electrocardiogram (ECG) monitoring is often used to assess premature atrial complex (PAC) and premature ventricular complex (PVC) frequency, but the diagnostic reliability is unknown. The objective of this study was to study the day-to-day variability of PAC and PVC frequency. METHODS AND RESULTS: We used 14-day full-disclosure mobile cardiac telemetry recordings without atrial fibrillation in 8245 US patients aged 17-103 years to calculate the diagnostic reliability of shorter ambulatory ECG recordings compared with 14-day averages. Over 14 days, 1853 patients had ≥500 PACs/day, 410 patients had ≥5000 PACs/day, and 197 patients had ≥10 000 PACs/day; 1640 patients had ≥500 PVCs/day, 354 patients had ≥5000 PVCs/day, and 175 patients had ≥10 000 PVCs/day. After 3 days, the estimated daily PAC frequency differed by ≥50% from the 14-day mean in 25% of patients; for PVCs, the corresponding duration was 7 days. Ten days of monitoring were needed to estimate PAC and PVC frequency within ±20% of the overall 14-day frequency in 80% of patients. For daily PAC and PVC frequencies ≥10 000, single-day estimation had a specificity of 99.3% [95% confidence interval (CI) 99.1-99.5] at a sensitivity of 76.6 (95% CI 70.1-80.4%) for PACs and a 99.6% (95% CI 99.4-99.7%) specificity at 79.4 (95% CI 72.7-85.2) sensitivity for PVCs. After 7 days, the sensitivity increased to 88.8% (95% CI 83.6-92.9) for PACs and 86.9% (95% CI 80.9-91.5%) for PVCs. CONCLUSION: While there is substantial daily variability across most PAC and PVC levels, findings of ≥10 000 PACs or PVCs are highly specific and do not need to be confirmed with longer recordings.

Sodium Intake and Incident Atrial Fibrillation in Individuals With Vascular Disease.

Importance: Numerous prospective cohort studies have reported a J-shaped association of urinary sodium excretion with cardiovascular events and mortality. Objective: To study the association between sodium intake and incident atrial fibrillation (AF). Design, Setting, and Participants: This cohort study included participants in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) multicenter, randomized clinical trials comparing the effect of ramipril 10 mg daily with telmisartan 80 mg daily, or their combination (ONTARGET) or 80 mg telmisartan daily with placebo (TRANSCEND) for the outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. ONTARGET and TRANSCEND included 31 546 participants with vascular disease or high-risk diabetes, and this study excluded participants without a urine sample for sodium measurement, missing data for key covariates, a history of AF, or AF detected in the first year after enrollment. Analyses were performed in July 2023 to May 2024. Exposure: Estimated sodium intake from a morning fasting urine sample (Kawasaki formula). Main Outcomes and Measures: The main outcome was incident AF. The association between estimated sodium intake and incident AF was modeled using multivariable adjusted Cox regression and cubic splines. Results: A total of 27 391 participants (mean [SD] age, 66.3 [7.2] years; 19 310 [70.5%] male) were included. Mean (SD) estimated sodium intake was 4.8 (1.6) g/d. During a mean (SD) follow-up of 4.6 (1.0) years, 1562 participants (5.7%) had incident AF. After multivariable adjustment, a J-shaped association between sodium intake and AF risk was observed (P for nonlinearity = .03). Sodium intake of 8 g/d or greater (3% of participants) was associated with incident AF (hazard ratio, 1.32; 95% CI, 1.01-1.74) compared with sodium intake of 4 to 5.99 g/d. Cubic splines showed that sodium intake greater than 6 g/d (19% of participants) was associated with a 10% increased AF risk per additional 1-g/d sodium intake (hazard ratio, 1.10; 95% CI, 1.03-1.18), but with no further lowering of AF risk at lower levels of sodium intake. Conclusions and Relevance: In this cohort study of sodium intake and AF risk, there was a J-shaped association between sodium intakes and AF risk in patients with cardiovascular disease or diabetes. Lowering sodium intake for AF prevention is best targeted at individuals who consume high sodium diets.

Reference ranges for ambulatory heart rate measurements in a middle-aged population.

BACKGROUND: Elevated heart rate (HR) predicts cardiovascular disease and mortality, but there are no established normal limits for ambulatory HR. We used data from the Swedish CArdioPulmonary Imaging Study to determine reference ranges for ambulatory HR in a middle-aged population. We also studied clinical correlates of ambulatory HR. METHODS: A 24-hour ECG was registered in 5809 atrial fibrillation-free individuals, aged 50-65 years. A healthy subset (n=3942) was used to establish reference values (excluding persons with beta-blockers, cardiovascular disease, hypertension, heart failure, anaemia, diabetes, sleep apnoea or chronic obstructive pulmonary disease).Minimum HR was defined as the lowest 1-minute HR. Reference ranges are reported as means±SDs and 2.5th-97.5th percentiles. Clinical correlates of ambulatory HR were analysed with multivariable linear regression. RESULTS: The average mean and minimum HRs were 73±9 and 48±7 beats per minute (bpm) in men and 76±8 and 51±7 bpm in women; the reference range for mean ambulatory HR was 57-90 bpm in men and 61-92 bpm in women. Average daytime and night-time HRs are also reported. Clinical correlates, including age, sex, height, body mass index, physical activity, smoking, alcohol intake, diabetes, hypertension, haemoglobin level, use of beta-blockers, estimated glomerular filtration rate, per cent of predicted forced expiratory volume in 1 s and coronary artery calcium score, explained <15% of the interindividual differences in HR. CONCLUSION: Ambulatory HR varies widely in healthy middle-aged individuals, a finding with relevance for the management of patients with a perception of tachycardia. Differences in ambulatory HR between individuals are largely independent of common clinical correlates.

Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

P-wave characteristics as electrocardiographic markers of atrial abnormality in prediction of incident atrial fibrillation - The Malmö Preventive Project.

BACKGROUND: P-wave indices reflect atrial abnormalities contributing to atrial fibrillation (AF). We aimed to assess a comprehensive set of P-wave characteristics for prediction of incident AF in a population-based setting. METHODS: Malmö Preventative Project (MPP) participants were reexamined in 2002-2006 with electrocardiographic (ECG) and echocardiographic examinations and followed for 5 years. AF-free subjects (n = 983, age 70 ± 5 years, 38% females) with sinus rhythm ECGs were included in the study. ECGs were digitally processed using the Glasgow algorithm. P-wave duration, axis, dispersion, P-terminal force in lead V1 and interatrial block (IAB) were evaluated. ECG risk score combining the morphology, voltage and length of P-wave (MVP score) was calculated. New-onset diagnoses of AF were obtained from nation-wide registers. RESULTS: During follow up, 66 patients (7%) developed AF. After adjustment for age and gender, the independent predictors of AF were abnormal P-wave axis > 75° (HR 1.63 CI95% 1.95-11.03) and MVP score 4 (HR 6.17 CI 95% 1.76-21.64), both correlated with LA area: Person r - 0.146, p < 0.001 and 0.192, p < 0.001 respectively. Advanced IAB (aIAB) with biphasic P-wave morphology in leads III and aVF was the most prevalent variant of aIAB and predicted AF in a univariate model (HR 2.59 CI 95% 1.02-6.58). CONCLUSION: P-wave frontal axis and MVP score are ECG-based AF predictors in the population-based cohort. Our study provides estimates for prevalence and prognostic importance of different variants of aIAB, providing a support to use biphasic P-wave morphology in lead aVF as the basis for aIAB definition.

Can 24 h of ambulatory ECG be used to triage patients to extended monitoring?

BACKGROUND: Access to long-term ambulatory recording to detect atrial fibrillation (AF) is limited for economical and practical reasons. We aimed to determine whether 24 h ECG (24hECG) data can predict AF detection on extended cardiac monitoring. METHODS: We included all US patients from 2020, aged 17-100 years, who were monitored for 2-30 days using the PocketECG device (MEDICALgorithmics), without AF ≥30 s on the first day (n = 18,220, mean age 64.4 years, 42.4% male). The population was randomly split into equal training and testing datasets. A Lasso model was used to predict AF episodes ≥30 s occurring on days 2-30. RESULTS: The final model included maximum heart rate, number of premature atrial complexes (PACs), fastest rate during PAC couplets and triplets, fastest rate during premature ventricular couplets and number of ventricular tachycardia runs ≥4 beats, and had good discrimination (ROC statistic 0.7497, 95% CI 0.7336-0.7659) in the testing dataset. Inclusion of age and sex did not improve discrimination. A model based only on age and sex had substantially poorer discrimination, ROC statistic 0.6542 (95% CI 0.6364-0.6720). The prevalence of observed AF in the testing dataset increased by quintile of predicted risk: 0.4% in Q1, 2.7% in Q2, 6.2% in Q3, 11.4% in Q4, and 15.9% in Q5. In Q1, the negative predictive value for AF was 99.6%. CONCLUSION: By using 24hECG data, long-term monitoring for AF can safely be avoided in 20% of an unselected patient population whereas an overall risk of 9% in the remaining 80% of the population warrants repeated or extended monitoring.

Markers of Atrial Myopathy in the General Population: Prevalence, Predictors, and Inter-Relations.

BACKGROUND: Atrial myopathy refers to structural and functional cardiac abnormalities associated with atrial fibrillation and stroke, but appropriate diagnostic criteria are lacking. OBJECTIVES: This study aimed to assess prevalence, clinical correlates, and overlap between potential atrial myopathy markers. METHODS: The population-based SCAPIS (Swedish CArdioPulmonary bioImage Study) prospectively included 6,013 subjects without atrial fibrillation with 24-hour electrocardiograms. Resting electrocardiograms measuring P-wave indices were collected at 1 screening site (n = 1,201), and a random sample (n = 385) had echocardiographic left atrial volume index (LAVi). Atrial myopathy markers were defined as ≥500 premature atrial complexes/24 h, LAVi ≥34 mL/m2, P-wave duration >120 milliseconds, or P-wave terminal force in V1 >4,000 ms·s. Clinical correlates included age, sex, body mass index, height, smoking, physical activity, coronary artery disease, diabetes, systolic blood pressure, antihypertensive medication, and low education. RESULTS: Atrial myopathy was common; 42% of the sample with all diagnostic modalities available had ≥1 atrial myopathy marker, but only 9% had 2 and 0.3% had ≥3. Only P-wave duration and LAVi were correlated (ρ = 0.10; P = 0.04). Clinical correlates of premature atrial complexes, P-wave indices, and LAVi differed; current smoking (34% increase; P < 0.001), systolic blood pressure (4%/mm Hg increase; P = 0.01), diabetes (35% increase; P = 0.001), and coronary artery disease (71% increase; P = 0.003) were associated with premature atrial complexes, physical activity ≥2 h/wk was associated with increased LAVi (ß-coefficient = 3.1; P < 0.0001) and body mass index was associated with P-wave duration (ß-coefficient = 0.4/kg/m2; P < 0.0001). CONCLUSIONS: In the general population, indirect markers of atrial myopathy are common but only weakly correlated, and their risk factor patterns are different. More studies are needed to accurately identify individuals with atrial myopathy with diagnostic methods.

Characterization of the Biosynthetic Gene Cluster for the Ribosomally Synthesized Cyclic Peptide Epichloëcyclins in Epichloë festucae.

The various grass-induced epichloëcyclins of the Epichloë spp. are ribosomally synthesized and post-translationally modified peptides (RiPPs), produced as small, secreted cyclopeptides from a single gene, gigA. Here, four clustered and coregulated genes (gigA, gigB, gigC, and kexB) with predicted roles in epichloëcyclin production in Epichloë festucae were evaluated through gene disruption. Subsequent chemical analysis indicates that GigB is a DUF3328 domain-containing protein associated with cyclization of epichloëcyclins; GigC is a methyltransferase enzyme responsible for N-methylation of desmethylepichloëcyclins; and KexB is a subtilisin-like enzyme, partly responsible for the propeptide cleavage of epichloëcyclin intermediates. Symbiotic effects on the host phenotype were not observed for gigA, gigC, or kexB mutants, although ΔgigB infection correlated with increased host tiller height and biomass, while only ΔkexB exhibited an effect on endophyte morphology. Disrupting epichloëcyclin biosynthesis showed negligible influence on the biosynthesis of E. festucae-associated alkaloids. Epichloëcyclins may perform other secondary metabolism functions in Epichloë and other fungi.

Ventricular tachycardia risk prediction with an abbreviated duration mobile cardiac telemetry.

Background: Ventricular tachycardia (VT) occurs intermittently, unpredictably, and has potentially lethal consequences. Objective: Our aim was to derive a risk prediction model for VT episodes ≥10 beats detected on 30-day mobile cardiac telemetry based on the first 24 hours of the recording. Methods: We included patients who were monitored for 2 to 30 days in the United States using full-disclosure mobile cardiac telemetry, without any VT episode ≥10 beats on the first full recording day. An elastic net prediction model was derived for the outcome of VT ≥10 beats on monitoring days 2 to 30. Potential predictors included age, sex, and electrocardiographic data from the first 24 hours: heart rate; premature atrial and ventricular complexes occurring as singlets, couplets, triplets, and runs; and the fastest rate for each event. The population was randomly split into training (70%) and testing (30%) samples. Results: In a population of 19,781 patients (mean age 65.3 ± 17.1 years, 43.5% men), with a median recording time of 18.6 ± 9.6 days, 1510 patients had at least 1 VT ≥10 beats. The prediction model had good discrimination in the testing sample (area under the receiver-operating characteristic curve 0.7584, 95% confidence interval 0.7340-0.7829). A model excluding age and sex had an equally good discrimination (area under the receiver-operating characteristic curve 0.7579, 95% confidence interval 0.7332-0.7825). In the top quintile of the score, more than 1 in 5 patients had a VT ≥10 beats, while the bottom quintile had a 98.2% negative predictive value. Conclusion: Our model can predict risk of VT ≥10 beats in the near term using variables derived from 24-hour electrocardiography, and could be used to triage patients to extended monitoring.

High-affinity iron uptake is required for optimal Epichloë festucae colonization of Lolium perenne and seed transmission.

Epichloë festucae uses a siderophore-mediated system to acquire iron, which is important to maintain endophyte-grass symbioses. Here we investigate the roles of the alternative iron acquisition system, reductive iron assimilation (RIA), via disruption of the fetC gene, which encodes a multicopper ferroxidase, either alone (i.e., ΔfetC) or in combination with disruption of the gene sidA, which encodes a siderophore biosynthesis enzyme (i.e., ΔfetC/ΔsidA). The phenotypic characteristics of these mutants were compared to ΔsidA and wild-type (WT) strains during growth under axenic culture conditions (in culture) and in symbiosis with the host grass, perennial ryegrass (in planta). Under iron deficiency, the colony growth rate of ΔfetC was slightly slower than that of WT, while the growth of ΔsidA and ΔfetC/ΔsidA mutants was severely suppressed. Siderophore analyses indicated that ΔfetC mutants hyperaccumulate ferriepichloënin A (FEA) at low iron concentrations and ferricrocin and FEA at higher iron concentrations. When compared to WT, all mutant strains displayed hyperbranching hyphal structures and a reduced ratio of Epichloë DNA to total DNA in planta. Furthermore, host colonization and vertical transmission through infection of the host seed were significantly reduced in the ΔfetC/ΔsidA mutants, confirming that high-affinity iron uptake is a critical process for Epichloë transmission. Thus, RIA and siderophore iron uptake are complementary systems required for the maintenance of iron metabolism, fungal growth, and symbiosis between E. festucae and perennial ryegrass.

Six-lead electrocardiography compared to single-lead electrocardiography and photoplethysmography of a wrist-worn device for atrial fibrillation detection controlled by premature atrial or ventricular contractions: six is smarter than one.

Background: Smartwatches are commonly capable to record a lead-I-like electrocardiogram (ECG) and perform a photoplethysmography (PPG)-based atrial fibrillation (AF) detection. Wearable technologies repeatedly face the challenge of frequent premature beats, particularly in target populations for screening of AF. Objective: To investigate the potential diagnostic benefit of six-lead ECG compared to single-lead ECG and PPG-based algorithm for AF detection of the wrist-worn device. Methods and results: From the database of DoubleCheck-AF 249 adults were enrolled in AF group (n = 121) or control group of SR with frequent premature ventricular (PVCs) or atrial (PACs) contractions (n = 128). Cardiac rhythm was monitored using a wrist-worn device capable of recording continuous PPG and simultaneous intermittent six-lead standard-limb-like ECG. To display a single-lead ECG, the six-lead ECGs were trimmed to lead-I-like ECGs. Two diagnosis-blinded cardiologists evaluated reference, six-lead and single-lead ECGs as "AF", "SR", or "Cannot be concluded". AF detection based on six-lead ECG, single-lead ECG, and PPG yielded a sensitivity of 99.2%, 95.7%, and 94.2%, respectively. The higher number of premature beats per minute was associated with false positive outcomes of single-lead ECG (18.80 vs. 5.40 beats/min, P < 0.01), six-lead ECG (64.3 vs. 5.8 beats/min, P = 0.018), and PPG-based detector (13.20 vs. 5.60 beats/min, P = 0.05). Single-lead ECG required 3.4 times fewer extrasystoles than six-lead ECG to result in a false positive outcome. In a control subgroup of PACs, the specificity of six-lead ECG, single-lead ECG, and PPG dropped to 95%, 83.8%, and 90%, respectively. The diagnostic value of single-lead ECG (AUC 0.898) was inferior to six-lead ECG (AUC 0.971) and PPG-based detector (AUC 0.921). In a control subgroup of PVCs, the specificity of six-lead ECG, single-lead ECG, and PPG was 100%, 96.4%, and 96.6%, respectively. The diagnostic value of single-lead ECG (AUC 0.961) was inferior to six-lead ECG (AUC 0.996) and non-inferior to PPG-based detector (AUC 0.954). Conclusions: A six-lead wearable-recorded ECG demonstrated the superior diagnostic value of AF detection compared to a single-lead ECG and PPG-based AF detection. The risk of type I error due to the widespread use of smartwatch-enabled single-lead ECGs in populations with frequent premature beats is significant.

ECG Modeling for Simulation of Arrhythmias in Time-Varying Conditions.

The present article proposes an ECG simulator that advances modeling of arrhythmias and noise by introducing time-varying signal characteristics. The simulator is built around a discrete-time Markov chain model for simulating atrial and ventricular arrhythmias of particular relevance when analyzing atrial fibrillation (AF). Each state is associated with statistical information on episode duration and heartbeat characteristics. Statistical, time-varying modeling of muscle noise, motion artifacts, and the influence of respiration is introduced to increase the complexity of simulated ECGs, making the simulator well suited for data augmentation in machine learning. Modeling of how the PQ and QT intervals depend on heart rate is also introduced. The realism of simulated ECGs is assessed by three experienced doctors, showing that simulated ECGs are difficult to distinguish from real ECGs. Simulator usefulness is illustrated in terms of AF detection performance when either simulated or real ECGs are used to train a neural network for signal quality control. The results show that both types of training lead to similar performance.

Sodium bicarbonate treatment for QRS widening in bupropion overdoses.

INTRODUCTION: Bupropion cardiotoxicity widens QRS complexes by inhibiting cardiac gap junctions. Sodium bicarbonate is the standard treatment for QRS widening from sodium channel blockade, but its effect on QRS widening in bupropion cardiotoxicity is not well-studied. METHODS: This is a retrospective cohort study of bupropion overdoses from 10 hospitals between January 2010 and June 2022. Patients with documented administration of sodium bicarbonate and QRS duration > 100 milliseconds on pre-bicarbonate electrocardiogram were included. Patients with no electrocardiogram within four hours of treatment or with baseline pre-overdose wide QRS and < 10 milliseconds widening from baseline were excluded. The primary outcome was a change in QRS duration between the pre-bicarbonate electrocardiogram and the first electrocardiogram after initial bicarbonate administration. Secondary outcomes included prevalence of post-bicarbonate QRS < 100 milliseconds, change in electrocardiogram intervals after total bicarbonate administration, and change in metabolic parameters and hemodynamics. Wilcoxon signed-rank testing was performed on the primary outcome. Linear regression modeling was performed to test for an association between change in QRS and bicarbonate dosing. RESULTS: Thirteen patients were included for final analysis. The median age was 32 years, and 54% were male. Six patients developed seizures; one developed ventricular tachycardia, and four received vasopressors. The median QRS and QTc pre-bicarbonate were 116 and 495 milliseconds, respectively. The median change in QRS duration was -2.0 milliseconds, which was not statistically significant (P = 0.42). The median bicarbonate dose administered before the first post-bicarbonate electrocardiogram was 100 milliequivalents. We did not identify an association between QRS change and bicarbonate dosing (P = 0.9, R-squared = 0.001). No patient had a QRS duration < 100 milliseconds after the initial bicarbonate dose. There was minimal change in QTc, electrolytes, heart rate, or blood pressure; alkalemia post-bicarbonate was achieved in eight patients. CONCLUSION: Sodium bicarbonate did not significantly decrease QRS duration in this small retrospective cohort of bupropion overdoses.

Survey of the Endophytic Bacteria Inhabiting Wild Daucus Seed Using 16S rRNA Gene Amplicon Sequencing.

We report a preliminary survey of the endophytic bacterial microbiota of seed from wild carrot (Daucus carota) using 16S rRNA gene amplicon sequencing. Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria were the most abundant phyla detected, while Bacillus, Massilia, Paenibacillus, Pantoea, Pseudomonas, Rhizobium, Sphingomonas, and Xanthomonas were the most abundant genera.

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic.

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

Epichloë seed transmission efficiency is influenced by plant defense response mechanisms.

Asexual Epichloë are endophytic fungi that form mutualistic symbioses with cool-season grasses, conferring to their hosts protection against biotic and abiotic stresses. Symbioses are maintained between grass generations as hyphae are vertically transmitted from parent to progeny plants through seed. However, endophyte transmission to the seed is an imperfect process where not all seeds become infected. The mechanisms underpinning the varying efficiencies of seed transmission are poorly understood. Host gene expression in response to Epichloë sp. LpTG-3 strain AR37 was examined within inflorescence primordia and ovaries of high and low endophyte transmission genotypes within a single population of perennial ryegrass. A genome-wide association study was conducted to identify population-level single nucleotide polymorphisms (SNPs) and associated genes correlated with vertical transmission efficiency. For low transmitters of AR37, upregulation of perennial ryegrass receptor-like kinases and resistance genes, typically associated with phytopathogen detection, comprised the largest group of differentially expressed genes (DEGs) in both inflorescence primordia and ovaries. DEGs involved in signaling and plant defense responses, such as cell wall modification, secondary metabolism, and reactive oxygen activities were also abundant. Transmission-associated SNPs were associated with genes for which gene ontology analysis identified "response to fungus" as the most significantly enriched term. Moreover, endophyte biomass as measured by quantitative PCR of Epichloë non-ribosomal peptide synthetase genes, was significantly lower in reproductive tissues of low-transmission hosts compared to high-transmission hosts. Endophyte seed-transmission efficiency appears to be influenced primarily by plant defense responses which reduce endophyte colonization of host reproductive tissues.

Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.

The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.

Elevated premature ventricular complex counts on 24-hour electrocardiogram predict incident atrial fibrillation and heart failure-A prospective population-based cohort study.

Background: Premature ventricular complexes (PVCs) are known to predict heart failure (HF) and premature atrial contractions (PACs) are known to predict atrial fibrillation (AF) and stroke. PVCs and PACs share pathophysiological mechanisms; however, the combined effects of PVCs and PACs on HF, AF, and stroke risk have not been studied. Objectives: To study elevated PVC counts on 24-hour electrocardiogram monitoring (24hECG) in relation to incidence of AF, HF, and stroke, and whether this effect is altered by PAC frequency. Methods: The prospective population-based Malmö Diet and Cancer study includes 24hECG registrations in 375 AF- and HF-free subjects (mean age 65 years, 55% women). During 17 years of follow-up there were 28 HF, 89 AF, and 28 stroke events. The hazard ratios (HR) of elevated PVC counts (defined as the top quartile, ≥77/24 hours) vs lower quartiles were assessed using multivariable adjusted Cox regression models. Results: Elevated PVC counts predicted incident AF (HR 1.9, 95% confidence interval [CI] 1.2-3.0) and HF (HR 3.1, 95% CI 1.4-7.0). Results were similar after adjustment for NT-proBNP and PACs. Multiform PVCs were associated with even higher risks (HR 2.8, 95% CI: 1.7-4.6 for AF; HR 5.0, 95% CI 2.2-11.7 for HF), as was the presence of both elevated PACs and PVCs (9% of the population, HR 4.1, 95% CI 2.4-6.8 for AF and HR 4.3, 95% CI 1.7-11.4 for HF). No significant association was found between elevated PVC counts and incident stroke. Conclusion: Elevated PVC counts predict incident AF and HF, particularly if PVCs are multiform or occur in combination with elevated PAC counts.