Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

Clinical characteristics and risk factors of connective tissue disease complicated with bronchiectasis and pulmonary infection.

The clinical data from 118 CTD patients with bronchiectasis were collected and categorized into two groups: pulmonary infection present (n = 67) and absent (n = 51), for comparative analysis of characteristics and risk factors. Then, we analyzed and compared their demographics, disease characteristics, and risk factors for infection. Among the whole cohort (n = 118), the incidence of pulmonary infections was 56.78%. The occurrence of rheumatoid arthritis, systemic lupus erythematosus, and vasculitis was found to be associated with an increased risk of pulmonary infection. Sputum culture identified Pseudomonas aeruginosa and Klebsiella pneumoniae as the predominant pathogens in the infected group. Notably, symptoms such as joint pains (p = 0.018) and morning stiffness (p = 0.017) were significantly more common in the infected group compared to the noninfected group. Moreover, our findings revealed that elevated levels of C-reactive protein and complement C3, along with bronchial expansion observed on high-resolution computed tomography (HRCT), were significant independent factors in the infection group. Conversely, pulmonary interstitial changes identified through HRCT (OR: 0.135, 95% CI: 0.030-0.612, p = 0.009) were significantly associated with the non-infection group. Overall, this study provides valuable insights into managing CTD patients with bronchiectasis, emphasizing early detection and tailored approaches to prevent and treat pulmonary infections for better outcomes.

Preparation of Activated Carbon Nanostructured Al@CuO with Low Static Sensitivity and High Reactivity.

The porous skeleton structure of oxidizers can effectively enlarge the contact area with fuels and boost the reactivity of thermites, but the overly complex preparation processes tend to limit their use to some extent. To overcome this issue, water-soluble starch and copper nitrate were used as a template to form a carbon skeleton copper oxide (C-CuO) after spray drying and calcination. By adding nanoaluminum into the spray drying process, the n-Al@C-CuO was prepared and compared with the physically mixed n-Al/C-CuO in the context. Scanning electron microscopy and differential scanning calorimetry were used to observe the morphology and analyze the thermal process. The pressure-time test and the electrostatic sensitivity test were used to measure the energy release properties and the safety of the thermites. Results indicated that the n-Al@C-CuO had 60.97 °C earlier initial exothermic temperature and 1.74 times higher peak pressure than that of the physically mixed sample. The n-Al@C-CuO was not ignited under 25 kV in the electrostatic sensitivity test, showing the great electrostatic safety of the sample. These findings are expected to facilitate the development of spray drying and promote energy release of traditional thermites.

Impact of Sarcoidosis on In-hospital Outcomes Among Patients with Atrial Fibrillation: A Nationwide Readmissions Database Analysis.

Sarcoidosis is a disease that involves multiple organs, including the cardiovascular system. While cardiac sarcoidosis has been increasingly recognized, the impact of sarcoidosis on atrial fibrillation (AF) is not well established. This study aimed to analyze the impact of sarcoidosis on in-hospital outcomes among patients who were admitted for a primary diagnosis of AF. Using the all-payer, nationally representative Nationwide Readmissions Database, our study included patients aged ≥18 years who were admitted for AF between 2017-2020. We stratified the cohort into two groups depending on the presence of sarcoidosis diagnosis. The in-hospital outcomes were assessed between the two groups via propensity score analysis. A total of 1031 (0.27%) AF patients with sarcoidosis and 387,380 (99.73%) AF patients without sarcoidosis were identified in our analysis. Our propensity score analysis of 1031 (50%) patients with AF and sarcoidosis and 1031 (50%) patients with AF but without sarcoidosis revealed comparable outcomes in early mortality (1.55% vs. 1.55%, P = 1.000), prolonged hospital stay (9.51% vs. 9.70%, P = .874), non-home discharge (7.95% vs. 9.89%, P = .108), and 30-day readmission (13.29% vs. 13.69%, P = .797) between the two groups. The cumulative cost of hospitalization was also similar in both groups ($12,632.25 vs. $12,532.63, P = .839). The in-hospital adverse event rates were comparable in both groups. Sarcoidosis is not a risk factor for poorer in-hospital outcomes following AF admission. These findings provide valuable insights into the effectiveness of the current guideline for AF management in patients with concomitant sarcoidosis and AF.

Impact of age on hospital outcomes after catheter ablation for ventricular tachycardia.

Background: The real-world data on the safety profile of ventricular tachycardia (VT) ablation among elderly patients is not well-established. This study aimed to evaluate the procedural outcomes among those aged 18-64 years versus those aged ≥65 years who underwent catheter ablation of VT. Method: Using the Nationwide Readmissions Database, our study included patients aged ≥18 years who underwent VT catheter ablation between 2017 and 2020. We divided the patients into non-elderly (18-64 years old) and elderly age groups (≥65 years old). We then analyzed the in-hospital procedural outcome and 30-day readmission between these two groups. Results: Our study included 2075 (49.1%) non-elderly patients and 2153 (50.9%) elderly patients who underwent VT ablation. Post-procedurally, elderly patients had significantly higher rates of prolonged index hospitalization (≥7 days; 35.5% vs. 29.3%, p < .01), non-home discharge (13.4% vs. 6.0%, p < .01), 30-day readmission (17.0% vs. 11.4%, p < .01), and early mortality (5.5% vs. 2.4%, p < .01). There was no significant difference in the procedural complications between two groups, namely vascular complications, hemopericardium/cardiac tamponade, cerebrovascular accident (CVA), major bleeding requiring blood transfusion, and systemic embolization. Through multivariable analysis, the elderly group was associated with higher odds of early mortality (OR: 7.50; CI 1.86-30.31, p = .01), non-home discharge (OR: 2.41; CI: 1.93-3.00, p < .01) and 30-day readmission (OR: 1.58; CI 1.32-1.89, p < .01). Conclusion: Elderly patients have worse in-hospital outcome, early mortality, non-home discharge, and 30-day readmission following catheter ablation for VT. There was no significant difference between elderly and non-elderly groups in the procedural complications.

Effects of returning paddy field to wetland on composition and stability of soil aggregates in the Yellow River Delta.

The composition and stability of soil aggregates are important indicators for measuring soil quality, which would be affected by land use changes. Taking wetlands with different returning years (2 and 15 years) in the Yellow River Delta as the research object, paddy fields and natural wetlands as control, we analyzed the changes in soil physicochemical properties and soil aggregate composition. The results showed that soil water content, total organic carbon, dissolved organic carbon and total phosphorus of the returning soil (0-40 cm) showed an overall increasing trend with returning period, while soil pH and bulk density was in adverse. There was no significant change in clay content, electrical conductivity, and total nitrogen content. The contents of macro-aggregates and micro-aggregates showed overall increasing and decreasing trend with returning period, respectively. The stability of aggregates in the topsoil (0-10 cm) increased with returning years. Geometric mean diameter and mean weight diameter increased by 8.9% and 40.4% in the 15th year of returning, respectively, while the mass proportion of >2.5 mm fraction decreased by 10.5%. There was no effect of returning on aggregates in subsoil (10-40 cm). Our results indicated that returning paddy field to wetland in the Yellow River Delta would play a positive role in improving soil structure and aggregate stability.

Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both In Vitro and In Vivo.

BRD4 is associated with a variety of human diseases, including breast cancer. The crucial roles of amino-terminal bromodomains (BDs) of BRD4 in binding with acetylated histones to regulate oncogene expression make them promising drug targets. However, adverse events impede the development of the BD inhibitors. BRD4 adopts an extraterminal (ET) domain, which recruits proteins to drive oncogene expression. We discovered a peptide inhibitor PiET targeting the ET domain to disrupt BRD4/JMJD6 interaction, a protein complex critical in oncogene expression and breast cancer. The cell-permeable form of PiET, TAT-PiET, and PROTAC-modified TAT-PiET, TAT-PiET-PROTAC, potently inhibits the expression of BRD4/JMJD6 target genes and breast cancer cell growth. Combination therapy with TAT-PiET/TAT-PiET-PROTAC and JQ1, iJMJD6, or Fulvestrant exhibits synergistic effects. TAT-PiET or TAT-PiET-PROTAC treatment overcomes endocrine therapy resistance in ERα-positive breast cancer cells. Taken together, we demonstrated that targeting the ET domain is effective in suppressing breast cancer, providing a therapeutic avenue in the clinic.

Purification and characterization of betacyanin monomers from Hylocereus polyrhizus peel: A comparative study of their antioxidant and antidiabetic activities with mechanistic insights.

Betacyanins have garnered escalating research interest for their promising bioactivities. However, substantial challenges in purification and separation have impeded a holistic comprehension of the distinct bioactivities of individual betacyanins and their underlying mechanisms. Herein, betanin and phyllocactin monomers with purity exceeding 95% were successfully obtained from Hylocereus polyrhizus peel using a feasible protocol. These monomers were subsequently employed for comparative bioactivity assessments to uncover underlying mechanisms and illuminate structure-activity relationships. Interestingly, phyllocactin exhibited superior antioxidant activities and 36.1% stronger inhibitory activity on α-glucosidase compared to betanin. Mechanistic studies have revealed that they function as mixed-type inhibitors of α-amylase and competitive inhibitors of α-glucosidase, with interactions predominantly driven by hydrogen bonding. Notably, phyllocactin demonstrated a greater binding affinity with enzymes than betanin, thereby substantiating its heightened inhibitory activity. Overall, our results highlight novel bioactivities of betacyanin monomers and provide profound insights into the intricate interplay between structures and properties.

Allele-specific DNA methylation and gene expression during shoot organogenesis in tissue culture of hybrid poplar.

Plant tissue regeneration is critical for genetic transformation and genome editing techniques. During the regeneration process, changes in epigenetic modifications accompany the cell fate transition. However, how allele-specific DNA methylation in two haplotypes contributes to the transcriptional dynamics during regeneration remains elusive. Here we applied an inter-species hybrid poplar (Populus alba × P. glandulosa cv. 84 K) as a system to characterize the DNA methylation landscape during de novo shoot organogenesis at allele level. Both direct and indirect shoot organogenesis showed a reduction in genome-wide DNA methylation. At gene level, non-expressed genes were hypermethylated in comparison with expressed genes. Among the genes exhibiting significant correlations between levels of DNA methylation and gene expression, the expression patterns of 75% of genes were negatively correlated with DNA methylation in the CG context, whereas the correlation patterns in the CHH context were the reverse. The allele-biased DNA methylation was consistent during shoot organogenesis, with fewer than one-thousandth of allele-specific methylation regions shifted. Analysis of allele-specific expression revealed that there were only 1909 genes showing phase-dependent allele-biased expression in the regeneration process, among which the allele pairs with greater differences in transcription factor binding sites at promoter regions exhibited greater differences in allele expression. Our results indicated a relatively independent transcriptional regulation in two subgenomes during shoot organogenesis, which was contributed by cis-acting genomic and epigenomic variations.

Predicting sepsis in-hospital mortality with machine learning: a multi-center study using clinical and inflammatory biomarkers.

BACKGROUND: This study aimed to develop and validate an interpretable machine-learning model that utilizes clinical features and inflammatory biomarkers to predict the risk of in-hospital mortality in critically ill patients suffering from sepsis. METHODS: We enrolled all patients diagnosed with sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV, v.2.0), eICU Collaborative Research Care (eICU-CRD 2.0), and the Amsterdam University Medical Centers databases (AmsterdamUMCdb 1.0.2). LASSO regression was employed for feature selection. Seven machine-learning methods were applied to develop prognostic models. The optimal model was chosen based on its accuracy, F1 score and area under curve (AUC) in the validation cohort. Moreover, we utilized the SHapley Additive exPlanations (SHAP) method to elucidate the effects of the features attributed to the model and analyze how individual features affect the model's output. Finally, Spearman correlation analysis examined the associations among continuous predictor variables. Restricted cubic splines (RCS) explored potential non-linear relationships between continuous risk factors and in-hospital mortality. RESULTS: 3535 patients with sepsis were eligible for participation in this study. The median age of the participants was 66 years (IQR, 55-77 years), and 56% were male. After selection, 12 of the 45 clinical parameters collected on the first day after ICU admission remained associated with prognosis and were used to develop machine-learning models. Among seven constructed models, the eXtreme Gradient Boosting (XGBoost) model achieved the best performance, with an AUC of 0.94 and an F1 score of 0.937 in the validation cohort. Feature importance analysis revealed that Age, AST, invasive ventilation treatment, and serum urea nitrogen (BUN) were the top four features of the XGBoost model with the most significant impact. Inflammatory biomarkers may have prognostic value. Furthermore, SHAP force analysis illustrated how the constructed model visualized the prediction of the model. CONCLUSIONS: This study demonstrated the potential of machine-learning approaches for early prediction of outcomes in patients with sepsis. The SHAP method could improve the interoperability of machine-learning models and help clinicians better understand the reasoning behind the outcome.

Impact of infective versus sterile transvenous lead removal on 30-day outcomes in cardiac implantable electronic devices.

BACKGROUND: Transvenous lead removal (TLR) is associated with increased mortality and morbidity. This study sought to evaluate the impact of TLR on in-hospital mortality and outcomes in patients with and without CIED infection. METHODS: From January 1, 2017, to December 31, 2020, we utilized the nationally representative, all-payer, Nationwide Readmissions Database to assess patients who underwent TLR. We categorized TLR as indicated for infection, if the patient had a diagnosis of bacteremia, sepsis, or endocarditis during the initial admission. Conversely, if none of these conditions were present, TLR was considered sterile. The impact of infective vs sterile indications of TLR on mortality and major adverse events was studied. RESULTS: Out of the total 25,144 patients who underwent TLR, 14,030 (55.8%) received TLR based on sterile indications, while 11,114 (44.2%) received TLR due to device infection, with 40.5% having systemic infection and 59.5% having isolated pocket infection. TLR due to infective indications was associated with a significant in-hospital mortality (5.59% vs 1.13%; OR = 5.16; 95% CI 4.33-6.16; p < 0.001). Moreover, when compared with sterile indications, TLR performed due to device infection was associated with a considerable risk of thromboembolic events including pulmonary embolism and stroke (OR = 3.80; 95% CI 3.23-4.47, p < 0.001). However, there was no significant difference in the conversion to open heart surgery (1.72% vs. 1.47%, p < 0.111), and infection was not an independent predictor of cardiac (OR = 1.12; 95% CI 0.97-1.29) or vascular complications (OR = 1.12; 95% CI 0.73-1.72) between the two groups. CONCLUSION: Higher in-hospital mortality and rates of thromboembolic events associated with TLR resulting from infective indications may warrant further pursuing this diagnosis in patients.

Effect of age on in-hospital outcomes of transvenous lead extraction for infected cardiac implantable electronic device.

BACKGROUND: The real-world data on the safety profile of transvenous lead extraction (TLE) for infected cardiac implantable electronic devices (CIED) among elderly patients is not well-established. This study aimed to evaluate the hospital outcomes between patients of different age groups who underwent TLE for infected CIED. METHOD: Using the Nationwide Readmissions Database, our study included patients aged ≥18 years who underwent TLE for infected CIED between 2017 and 2020. We divided the patients into four groups: Group A. Young (<50 years), Group B. Young intermediate (50-69 years old), Group C. Older intermediate (70-79 years old), and Group D. Octogenarian (≥80 years old). We then analyzed the in-hospital outcome and 30-day readmission between these age groups. RESULTS: A total of 10,928 patients who were admitted for TLE of infected CIED were included in this study: 982 (9.0%) patients in group A, 4,234 (38.7%) patients in group B, 3,204 (29.3%) patients in group C and 2,508 (23.0%) of patients in group D. Our study demonstrated that the risk of early mortality increased with older age (Group B vs. Group A: OR: 1.92, 95% CI: 1.19-3.09, p < .01; Group C vs. Group A: OR: 2.47, 95% CI: 1.51-4.04, p < .01; Group D vs. Group A: OR: 2.82, 95% CI: 1.69-4.72, p < .01). The risk of non-home discharge also increased in elderly groups (Group B vs. Group A: OR: 1.89; 95% CI: 1.52-2.36; p < .01; Group C vs. Group A: OR: 2.82; 95% CI 2.24-3.56; p < .01; Group D vs. Group A: OR: 4.16; 95% CI: 3.28-5.28; p < .01). There was no significant difference in hospitalization length and 30-day readmission between different age groups. Apart from a higher rate of open heart surgery in group A, the procedural complications were comparable between these age groups. CONCLUSION: Elderly patients had worse in-hospital outcomes in early mortality and non-home discharge following the TLE for infected CIED. There was no significant difference between elderly and non-elderly groups in prolonged hospital stay and 30-day readmission. Elderly patients did not have a higher risk of procedural complications.

Heterostructure CoS2/MoS2 Nanosheets as a Dual-Active Electrocatalyst for the Oxygen Evolution Reaction.

Cost-effective and earth-abundant oxygen evolution reaction (OER) electrocatalysts are an incredible research hotspot in numerous energy storage and conversion technology fields. Herein, CoS2/MoS2 nanosheets supported by carbon cloth as a dual-active CC@CoS2/MoS2 heterostructure electrocatalyst is prepared through a simple solvothermal method. The catalyst demonstrates admirable OER performance in 1 M KOH solution with a low overpotential of 243 mV at a current density of 10 mA cm-2 and a minor Tafel slope of 109 mV dec-1, displaying honorable stability after 1000 cyclic voltammetry (CV) cycles and long-term robustness over 60 h. Theoretical calculations further ascertain that the rate-determining step of the electrocatalytic course of the CC@CoS2/MoS2 heterostructure is the conversion *O + OH- → *OOH + e- with a lower energy barrier of 1.49 eV due to the heterojunction established by CoS2 and MoS2, which can promote the OER performance of electrocatalysts. The actual identification of the catalytic mechanism in the heterostructure is conducive to the improvement of electrocatalysis applications in the OER.

Thirty-day readmission after catheter ablation for ventricular tachycardia: associated factors and outcomes.

BACKGROUND: Patients with ventricular tachycardia (VT) who require VT ablation are at high risk for readmission. This study aimed to identify the causes and outcomes of 30-day readmission after VT ablation and to analyze the predictors of recurrent VT that required rehospitalization. METHODS: Using the Nationwide Readmission Database, our study included patients aged ≥ 18 years who underwent VT catheter ablation between 2017 and 2020. Based on the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), we identified the causes of 30-day readmission by organ systems and analyzed their outcomes. Additional analysis was performed to determine the independent predictors of 30-day readmission for recurrent VT. RESULTS: Of the 4228 patients who underwent VT ablation, 14.2% were readmitted within 30 days of the procedure. The most common cause of readmission was cardiac events (73.6%). Among the cardiac-related readmissions, recurrent VT (47.7%) and congestive heart failure (CHF) (12.9%) were the most common etiologies. Among the readmissions, patients readmitted for CHF had the highest rate of readmission mortality (9.2%). Of the patients readmitted within 30 days of the procedure, 278 patients (6.8%) were readmitted for recurrent VT. Via multivariable analysis, CHF (OR: 1.97; 95% CI: 1.12-3.47; P = 0.02) and non-elective index admissions (OR: 1.63; 95% CI: 1.04-2.55; P = 0.03) were identified as the independent predictors predictive of 30-day readmissions for recurrent VT. CONCLUSIONS: Recurrent VT was the most common cause of readmission after the VT ablation procedure, and CHF and non-elective index admissions were the significant predictors of these early readmissions. Readmission due to CHF had the highest mortality rate during readmission.

Predictive value of triple negative breast cancer based on DCE-MRI multi-phase full-volume ROI clinical radiomics model.

BACKGROUND: Since no studies compared the value of radiomics features of distinct phases of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting triple-negative breast cancer (TNBC). PURPOSE: To identify the optimal phase of DCE-MRI for diagnosing TNBC and, in combination with clinical factors, to develop a clinical-radiomics model to well predict TNBC. MATERIAL AND METHODS: This retrospective study included 158 patients with pathology-confirmed breast cancer, including 38 cases of TNBC. The patients were randomly divided into the training and validation set (7:3). Eight radiomics models were built based on eight DCE-MR phases, and their performances were evaluated using receiver operating characteristic curve (ROC) and DeLong's test. The Radscore derived from the best radiomics model was integrated with independent clinical risk factors to construct a clinical-radiomics predictive model, and evaluate its performance using ROC analysis, calibration, and decision curve analyses. RESULTS: WHO classification, margin, and T2-weighted (T2W) imaging signals were significantly correlated with TNBC and independent risk factors for TNBC (P<0.05). The clinical model yielded areas under the curve (AUCs) of 0.867 and 0.843 in the training and validation sets, respectively. The radiomics model based on DCEphase7 achieved the highest efficacy, with an AUC of 0.818 and 0.777. The AUC of the clinical-radiomics model was 0.936 and 0.886 in the training and validation sets, respectively. The decision curve showed the clinical utility of the clinical-radiomics model. CONCLUSION: The radiomics features of DCE-MRI had the potential to predict TNBC and could improve the performance of clinical risk factors for preoperative personalized prediction of TNBC.

Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski's rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4'-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4'-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma.

Single-cell transcriptome and metagenome profiling reveals the genetic basis of rumen functions and convergent developmental patterns in ruminants.

The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell-cell and microbiome-cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.