Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study.

Background: Several studies have pointed to the critical role of gut microbiota (GM) and their metabolites in Hirschsprung disease (HSCR) pathogenesis. However, the detailed causal relationship between GM and HSCR remains unknown. Methods: In this study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between GM and HSCR, based on the MiBioGen Consortium's genome-wide association study (GWAS) and the GWAS Catalog's HSCR data. Reverse MR analysis was performed subsequently, and the sensitivity analysis, Cochran's Q-test, MR pleiotropy residual sum, outlier (MR-PRESSO), and the MR-Egger intercept were used to analyze heterogeneity or horizontal pleiotropy. 16S rDNA sequencing and targeted mass spectrometry were developed for initial validation. Results: In the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23-5.74, p = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18-0.73, p = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11-0.91, p = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06-0.78, p = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09-0.8, p = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04-0.66, p = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21-0.98, p = 0.04) were protective factors for HSCR, which had no heterogeneity or horizontal pleiotropy. However, reverse MR analysis showed that HSCR (OR: 1.02, 95%CI: 1-1.03, p = 0.049) is the risk factor for Eggerthella. Furthermore, some of the above microbiota and short-chain fatty acids (SCFAs) were altered in HSCR, showing a correlation. Conclusion: Our analysis established the relationship between specific GM and HSCR, identifying specific bacteria as protective or risk factors. Significant microbiota and SCFAs were altered in HSCR, underlining the importance of further study and providing new insights into the pathogenesis and treatment.

A smartwatch sphygmomanometer-based model for predicting short-term new-onset hypertension in individuals with high-normal blood pressure: a cohort study.

OBJECTIVES: The objective was to utilize a smartwatch sphygmomanometer to predict new-onset hypertension within a short-term follow-up among individuals with high-normal blood pressure (HNBP). METHODS: This study consisted of 3180 participants in the training set and 1000 participants in the validation set. Participants underwent both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) using a smartwatch sphygmomanometer. Multivariable Cox regressions were used to analyze cumulative events. A nomogram was constructed to predict new-onset hypertension. Discrimination and calibration were assessed using the C-index and calibration curve, respectively. RESULTS: Among the 3180 individuals with HNBP in the training set, 693 (21.8%) developed new-onset hypertension within a 6-month period. The nomogram for predicting new-onset hypertension had a C-index of 0.854 (95% CI, 0.843-0.867). The calibration curve demonstrated good agreement between the nomogram's predicted probabilities and actual observations for short-term new-onset hypertension. In the validate dataset, during the 6-month follow-up, the nomogram had a good C-index of 0.917 (95% CI, 0.904-0.930) and a good calibration curve. As the score increased, the risk of new-onset hypertension significantly increased, with an HR of 8.415 (95% CI: 5.153-13.744, p = .000) for the middle-score vs. low-score groups and 86.824 (95% CI: 55.071-136.885, p = .000) for the high-score vs. low-score group. CONCLUSIONS: This study provides evidence for the use of smartwatch sphygmomanometer to monitor blood pressure in individuals at high risk of developing new-onset hypertension in the near future. TRIAL REGISTRATION: ChiCTR2200057354.

Long-term simulated microgravity fosters carotid aging-like changes via Piezo1.

AIMS: Elucidating the impacts of long-term spaceflight on cardiovascular health is urgently needed in face of the rapid development of human space exploration. Recent reports including the NASA Twins Study on vascular deconditioning and aging of astronauts in spaceflight are controversial. The aims of this study were to elucidate whether long-term microgravity promotes vascular aging and the underlying mechanisms. METHODS AND RESULTS: Hindlimb unloading (HU) by tail suspension was used to simulate microgravity in rats and mice. The dynamic changes of carotid stiffness in rats during 8 weeks of HU were determined. Simulated microgravity led to carotid artery aging-like changes as evidenced by increased stiffness, thickness, fibrosis, and elevated senescence biomarkers in the HU rats. Specific deletion of the mechanotransducer Piezo1 in vascular smooth muscles significantly blunted these aging-like changes in mice. Mechanistically, mechanical stretch-induced activation of Piezo1 elevated microRNA-582-5p in vascular smooth muscle cells, with resultant enhanced synthetic cell phenotype and increased collagen deposition via PTEN/PI3K/Akt signalling. Importantly, inhibition of miRNA-582-5p alleviated carotid fibrosis and stiffness not only in HU rats but also in aged rats. CONCLUSIONS: Long-term simulated microgravity induces carotid aging-like changes via the mechanotransducer Piezo1-initiated and miRNA-mediated mechanism.

An overlooked oxidation mechanism of toluene: computational predictions and experimental validations.

Secondary organic aerosols (SOAs) influence the Earth's climate and threaten human health. Aromatic hydrocarbons (AHs) are major precursors for SOA formation in the urban atmosphere. However, the revealed oxidation mechanism dramatically underestimates the contribution of AHs to SOA formation, strongly suggesting the importance of seeking additional oxidation pathways for SOA formation. Using toluene, the most abundant AHs, as a model system and the combination of quantum chemical method and field observations based on advanced mass spectrometry, we herein demonstrate that the second-generation oxidation of AHs can form novel epoxides (TEPOX) with high yield. Such TEPOX can further react with H2SO4 or HNO3 in the aerosol phase to form less-volatile compounds including novel non-aromatic and ring-retaining organosulfates or organonitrates through reactive uptakes, providing new candidates of AH-derived organosulfates or organonitrates for future ambient observation. With the newly revealed mechanism, the chemistry-aerosol box modeling revealed that the SOA yield of toluene oxidation can reach up to 0.35, much higher than 0.088 based on the original mechanism under the conditions of pH = 2 and 0.1 ppbv NO. This study opens a route for the formation of reactive uptake SOA precursors from AHs and significantly fills the current knowledge gap for SOA formation in the urban atmosphere.

Stack growth of wafer-scale van der Waals superconductor heterostructures.

Two-dimensional (2D) van der Waals (vdW) heterostructures have attracted considerable attention in recent years1-5. The most widely used method of fabrication is to stack mechanically exfoliated micrometre-sized flakes6-18, but this process is not scalable for practical applications. Despite thousands of 2D materials being created, using various stacking combinations1-3,19-21, hardly any large 2D superconductors can be stacked intact into vdW heterostructures, greatly restricting the applications for such devices. Here we report a high-to-low temperature strategy for controllably growing stacks of multiple-layered vdW superconductor heterostructure (vdWSH) films at a wafer scale. The number of layers of 2D superconductors in the vdWSHs can be precisely controlled, and we have successfully grown 27 double-block, 15 triple-block, 5 four-block and 3 five-block vdWSH films (where one block represents one 2D material). Morphological, spectroscopic and atomic-scale structural analyses reveal the presence of parallel, clean and atomically sharp vdW interfaces on a large scale, with very little contamination between neighbouring layers. The intact vdW interfaces allow us to achieve proximity-induced superconductivity and superconducting Josephson junctions on a centimetre scale. Our process for making multiple-layered vdWSHs can easily be generalized to other situations involving 2D materials, potentially accelerating the design of next-generation functional devices and applications22-24.

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome.

BACKGROUND: The validation of various risk scores in elderly patients with comorbid atrial fibrillation (AF) and acute coronary syndrome (ACS) has not been reported. The present study compared the predictive performance of existing risk scores in these patients. METHODS: A total of 1252 elderly patients with AF and ACS comorbidities (≥ 65 years old) were consecutively enrolled from January 2015 to December 2019. All patients were followed up for one year. The predictive performance of risk scores in predicting bleeding and thromboembolic events was calculated and compared. RESULTS: During the 1-year follow-up, 183 (14.6%) patients had thromboembolic events, 198 (15.8%) patients had BARC class ≥ 2 bleeding events, and 61 (4.9%) patients had BARC class ≥ 3 bleeding events. For the BARC class ≥ 3 bleeding events, discrimination of the existing risk scores was low to moderate, PRECISE-DAPT (C-statistic: 0.638, 95% CI: 0.611-0.665), ATRIA (C-statistic: 0.615, 95% CI: 0.587-0.642), PARIS-MB (C-statistic: 0.612, 95% CI: 0.584-0.639), HAS-BLED (C-statistic: 0.597, 95% CI: 0.569-0.624) and CRUSADE (C-statistic: 0.595, 95% CI: 0.567-0.622). However, the calibration was good. PRECISE-DAPT showed a higher integrated discrimination improvement (IDI) than PARIS-MB, HAS-BLED, ATRIA, and CRUSADE (P < 0.05) and the best decision curve analysis (DCA). For thromboembolic events, the discrimination of GRACE (C-statistic: 0.636, 95% CI: 0.608-0.662) was higher than CHA2DS2-VASc (C-statistic: 0.612, 95% CI: 0.584-0.639), OPT-CAD (C-statistic: 0.602, 95% CI: 0.574-0.629) and PARIS-CTE (C-statistic: 0.595, 95% CI: 0.567-0.622). The calibration was good. Compared to OPT-CAD and PARIS-CTE, the IDI of the GRACE score slightly improved (P < 0.05). However, NRI analysis showed no significant difference. DCA showed that the clinical practicability of thromboembolic risk scores was similar. CONCLUSIONS: The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS. PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class ≥ 3 bleeding events. The GRACE score showed a slight advantage in predicting thrombotic events.

A Binary Solution Strategy Enables High-Efficiency Quasi-2D Perovskite Solar Cells with Excellent Thermal Stability.

Quasi-two-dimensional (2D) perovskites are highly promising light-harvesting materials for commercialization of perovskite solar cells (PSCs) owing to the excellent materials stability. However, the coexistence of multiple n-value species in 2D perovskites often causes increased complexities in crystallization that can negatively affect the eventual photovoltaic performance. Herein, we present a binary solution based strategy via introducing nontoxic and widely accessible CH3COOH (HAc) as a co-solvent for preparing high-quality 2D perovskite films. Based on a 2D perovskite model system, (AA)2MA4Pb5I16 (n = 5), we show that the prenucleation and grain growth kinetics are appreciably modified with HAc, which benefits from the strong electron-donating ability of HAc with the key component of PbI2, leading to formation of favorable cluster aggregates and resultant modulation of crystal growth. With the HAc-based method, the devices yield a boosted photovoltaic efficiency of 18.55% with an impressive photovoltage of 1.26 V. The champion cells exhibit a supreme thermal stability, showing <3% efficiency degradation under continuous thermal aging for 800 h.

Growth of wafer-scale chromium sulphide and selenide semiconductor films.

Two-dimensional (2D) transition metal chalcogenides have attracted enormous attention due to their stunning properties and great prospects for applications. Most of the reported 2D materials have layered structure, and non-layered transition metal chalcogenides are rare. Particularly, chromium chalcogenides are highly complexed in terms of structural phases. Researches on their representative chalcogenides, Cr2S3and Cr2Se3, are insufficient and most of them focus on individual crystal grains. In this study, large-scale Cr2S3and Cr2Se3films with controllable thickness are successfully grown, and their crystalline qualities are confirmed by multiple characterizations. Moreover, the thickness-dependent Raman vibrations are investigated systematically, presenting slight redshift with increasing thickness. The fundamental physical properties of grown Cr2S3and Cr2Se3films, including optical bandgap, activation energy and electrical properties, are measured with different thicknesses. The 1.9 nm thick Cr2S3and Cr2Se3films show narrow optical bandgap of 0.732 and 0.672 eV, respectively. The electrical properties of Cr2S3films demonstratep-type semiconductor behaviours, while the Cr2Se3films exhibit no gate response. This work can provide a feasible method for growing large-scale Cr2S3and Cr2Se3films, and reveal fundamental information of their physical properties, which is helpful for future applications.

Sensitive detection of single-nucleotide polymorphisms by conjugated polymers for personalized treatment of hypertension.

Genetic variants among individuals have been associated with ineffective control of hypertension. Previous work has shown that hypertension has a polygenic nature, and interactions between these loci have been associated with variations in drug response. Rapid detection of multiple genetic loci with high sensitivity and specificity is needed for the effective implementation of personalized medicine for the treatment of hypertension. Here, we used a cationic conjugated polymer (CCP)-based multistep fluorescence resonance energy transfer (MS-FRET) technique to qualitatively analyze DNA genotypes associated with hypertension in the Chinese population. Assessment of 10 genetic loci using this technique successfully identified known hypertensive risk alleles in a retrospective study of whole-blood samples from 150 patients hospitalized with hypertension. We then applied our detection method in a prospective clinical trial of 100 patients with essential hypertension and found that personalized treatment of patients with hypertension based on results from the MS-FRET technique could effectively improve blood pressure control rate (94.0% versus 54.0%) and shorten the time duration to controlling blood pressure (4.06 ± 2.10 versus 5.82 ± 1.84 days) as compared with conventional treatment. These results suggest that CCP-based MS-FRET genetic variant detection may assist clinicians in rapid and accurate classification of risk in patients with hypertension and improve treatment outcomes.

Selective Electrochemical Synthesis of 9-Aryl-10-sulfonyl Substituted Phenanthrene from Alkynes and Sulfonyl Hydrazides.

An efficient electrochemical synthesis of sulfonated phenanthrenes via the reaction of internal alkynes with sulfonyl hydrazides has been established. The protocol does not require a metal catalyst or external oxidants, providing a green and mild route to functionalized phenanthrenes. Moreover, the compatibility of various functional groups and decagram-scale experimental conditions demonstrate the practicality of the electrochemical strategy.

Controllable growth of wafer-scale monolayer transition metal dichalcogenides ternary alloys with tunable band gap.

The tuning of band gap is very important for the application of two-dimensional (2D) materials in optoelectronic devices. Alloying of 2D transition metal dichalcogenides (TMDCs) is an important way to tune the wide band gap. In this study, we report a multi-step vapor deposition method to grow monolayer TMDC ternary alloy films with wafer scale, including Mo1-xWxS2, Mo1-xWxSe2and MoS2xSe2(1-x), which are accurately controllable in the elemental proportion (xis from 0 to 1). The band gap of the three 2D ternary alloy materials are continuously tuned for the whole range of metal and chalcogen compositions. The metal compositions are controlled by the as-deposited thickness. Raman, photoluminescence, elemental maps and TEM show the high spatial homogeneity in the compositions and optical properties across the whole wafer. The band gap can be continuously tuned from 1.86 to 1.99 eV for Mo1-xWxS2, 1.56 to 1.65 eV for Mo1-xWxSe2, 1.56 to 1.86 eV for MoS2xSe2(1-x). Electrical transport measurements indicate that Mo1-xWxS2and MoS2xSe2(1-x)monolayers shown-type semiconductor behaviors, and the carrier types of Mo1-xWxSe2can be tuned asn-type, bipolar andp-type. Moreover, this control process can be easily generalized to other 2D alloy films, even to quaternary or multi-element alloy materials. Our study presents a promising route for the preparation of large-scale homogeneous monolayer TMDC alloys and the application for future functional devices.

Association Between Familial Hypercholesterolemia and Risk of Cardiovascular Events and Death in Different Cohorts: A Meta-Analysis of 1.1 Million Subjects.

Background and Aims: The association of familial hypercholesterolemia (FH) with risk of cardiovascular events (CVE) and death in different cohorts is controversial. We aimed to assess the risk of CVE and death in patients with FH in different cohorts, including CHD and ACS patients, White and Asian, different diagnostic criteria. Methods: We searched PubMed, MEDLINE, and Web of Science electronic databases through May 2021 to identify cohort studies of CVE and death in patients with FH. Results: We found 18 eligible studies with 1,139,788 participants, including 34,261 patients. There were 31,287 ACS patients, of whom 2,338 were combined with FH. Randomized-effects meta-analysis showed that in patients with FH, relative risk (RR) of CVE and death was 1.87 (95% CI 1.21-2.88), among which CVE was 2.14 (95%CI 1.26-3.64), all-cause of death RR = 1.12 (95% CI 0.89-1.41), and cardiac death RR = 1.03 (95% CI 0.59-1.79). Risk of CVE and death in general population with FH was 2.85 (95% CI 0.72-11.21), hyperlipidemia population RR = 1.59 (95% CI 1.05-2.41), coronary heart disease patients (CHD) RR = 1.46 (95% CI 1.24-1.72), and acute coronary syndrome patients (ACS) RR = 1.71 (95% CI 1.19-2.46). Among ACS patients, the RR of CVE in patients with FH was 1.91 (95% CI 1.55-2.35), the RR of all-cause of death was 1.03 (95% CI 0.80-1.32), and the RR of cardiac death was 1.03 (95% CI 0.59-1.79). The risk of CVE and death in ACS patients with FH in White was 1.69 (95% CI 1.09-2.64) and Asian 1.90 (95% CI 1.31-2.75). RR in patients with Dutch Lipid Network criteria (DLCN) ≥6 vs. <3 points was higher (RR = 2.24, 95% CI 1.69-2.97). RR for long-term follow-up was 1.68 (95% CI 1.09-2.61) and for short-term follow-up was 1.80 (95% CI 1.16-2.78). The results of the overall population were similar, but RR for overall population during a short-term follow-up was 1.49 (95% CI 0.81-2.73). We followed PRISMA checklist to complete meta-analysis. Conclusions: The risk of CVE and death was increased in patients with CHD, especially in patients with ACS. DLCN ≥ 6 points was suggested for clinical diagnosis of FH. The risk of long-term and short-term CVE and death increased in ACS patients with FH. Registration Number: INPLASY2021110010.

Transition of Metabolic Phenotypes and Risk of Atrial Fibrillation According to BMI: Kailuan Study.

Objective: Atrial fibrillation (AF) is associated with both obesity and its metabolic consequences. However, there is a paucity of information on whether the dynamic change of metabolic health and obesity phenotypes affect the risk of AF. We aimed to prospectively examine the association between metabolic health and its change over time and AF risk across body mass index (BMI) categories. Methods: A total of 58,483 participants without history of cancer, and cardiovascular diseases from the Kailuan study were included in the present study. Transition of metabolic phenotypes was evaluated between 1st survey (2006-2007) and the 2nd survey (2008-2009). The hazard ratios (HRs) and 95% confidence intervals (CIs) for AF were assessed by Cox proportional hazards regression. Results: During a median follow-up of 3 years, we documented 580 cases of AF. Compared with metabolically healthy individuals with normal weight, the multivariable-adjusted hazard ratios for metabolically healthy and unhealthy overweight/obese were 1.27 (95% CI: 1.01, 1.59) and 1.37 (95% CI: 1.09, 1.72), respectively. However, when transition was taken into account, overweight/obese people who maintained metabolically healthy status were not associated with increased long-term risk (HR, 1.11;95% CI: 0.70, 1.78), whereas participants who converted from metabolically healthy overweight/obese status to an unhealthy phenotype had higher AF risk than those who maintained metabolically healthy normal weight (HR 1.59, 95% CI: 1.11, 2.26). When BMI and metabolically healthy status were updated over the course of the study, significant short-term elevations in AF risk were associated with individuals with stable MU-OW/OB status. Conclusion: In this community-based cohort study, metabolically healthy overweight/obese individuals have increased risks of AF. Obesity remains a risk factor for AF independent of major metabolic factors. Our data further suggested that metabolic phenotype was a dynamic condition, and maintenance of metabolic health and normal weight might alleviate the risk of AF.

BioCaster in 2021: automatic disease outbreaks detection from global news media.

SUMMARY: BioCaster was launched in 2008 to provide an ontology-based text mining system for early disease detection from open news sources. Following a 6-year break, we have re-launched the system in 2021. Our goal is to systematically upgrade the methodology using state-of-the-art neural network language models, whilst retaining the original benefits that the system provided in terms of logical reasoning and automated early detection of infectious disease outbreaks. Here, we present recent extensions such as neural machine translation in 10 languages, neural classification of disease outbreak reports and a new cloud-based visualization dashboard. Furthermore, we discuss our vision for further improvements, including combining risk assessment with event semantics and assessing the risk of outbreaks with multi-granularity. We hope that these efforts will benefit the global public health community. AVAILABILITY AND IMPLEMENTATION: BioCaster web-portal is freely accessible at http://biocaster.org.

Elevated levels of body mass index and waist circumference, but not high variability, are associated with an increased risk of atrial fibrillation.

BACKGROUND: Although obesity has been associated with risk of atrial fibrillation (AF), the associations of variability of obesity measures with AF risk are uncertain, and longitudinal studies among Chinese population are still lacking. We aimed to evaluate the impacts of obesity and variability of body mass index (BMI) and waist circumference (WC) on the risk of atrial fibrillation (AF) in a large Chinese cohort study. METHODS: A total of 44,135 participants of the Kailuan Study who were free of cancer and cardiovascular disease and underwent three consecutive surveys from 2006 to 2010 were followed for incident AF until 2020. Average BMI and WC over time and variability were calculated. Cox proportional hazards regression models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of obesity and variability in BMI and WC with AF risk. RESULTS: During a mean follow-up of 9.68 years, there were 410 cases of incident AF. In multivariable-adjusted models, compared with normal BMI/WC, individuals with general obesity and abdominal obesity had increased risk of AF, with corresponding HRs of 1.73 (95% CI: 1.31-2.30) and 1.38 (95% CI: 1.11-1.60), respectively. The short-term elevation in AF risk persisted for the obese even after adjustment for updated biologic intermediaries and weight. Variability in BMI and WC were not associated with the risk of AF. The restricted cubic spline models indicated significant linear relationships between levels of WC and BMI and risk of AF. CONCLUSIONS: Elevated levels of BMI and WC were associated with an increased risk of AF, whereas variability in BMI and WC were not. Therefore, achieving optimal levels of BMI and WC could be valuable in AF prevention.

Synthesis of polyallenoates through copper-mediated cross-coupling of dialkynes and bis-α-diazoesters.

The copper-catalyzed cross-coupling of alkynes and α-diazoesters has been applied in the synthesis of polyallenoates for the first time. The polymerization tolerated various functional groups and afforded the polyallenoates with high molecular weight. With chiral guanidinium bromide as a ligand, the axial chirality of the allene moiety could be generated with high enantioselectivity during the polymerization process.

Tuning the morphology of 2D transition metal chalcogenides via oxidizing conditions.

Two-dimensional transition metal chalcogenides (TMCs) are emerging as an intriguing platform to realize nascent properties in condensed matter physics, materials science and device engineering. Controllable growing of TMCs becomes increasingly important, especially for the layer number, doping, and morphology. Here, we successfully tune the morphology of MoS2, MoSe2, WS2and WSe2, from homogenous films to individual single crystalline grains only via changing the oxidizing growth conditions. The oxidization degrees are determined by the oxygen that adsorbed on substrates and the oxygen concentrations in reaction gas together. We find the homogenous films are easily formed under the reductive conditions, triangular grains prefer the weak oxidizing conditions, and medium oxidizing conditions bring in dendritic grains with higher oxygen doping and inhomogenous photoluminescence intensities from edge to interior regions shown in the dendritic grains. These growth rules under different oxidizing conditions are easily generalized to other TMCs, which also show potential for growing specific TMCs with designed oxygen doping levels.

Machine learning predicts the effect of food on orally administered medicines.

Food-mediated changes to drug absorption, termed the food effect, are hard to predict and can have significant implications for the safety and efficacy of oral drug products in patients. Mimicking the prandial states of the human gastrointestinal tract in preclinical studies is challenging, poorly predictive and can produce difficult to interpret datasets. Machine learning (ML) has emerged from the computer science field and shows promise in interpreting complex datasets present in the pharmaceutical field. A ML-based approach aimed to predict the food effect based on an extensive dataset of over 311 drugs with more than 20 drug physicochemical properties, referred to as features. Machine learning techniques were tested; including logistic regression, support vector machine, k-Nearest neighbours and random forest. First a standard ML pipeline using a 80:20 split for training and testing was tried to predict no food effect, negative food effect and positive food effect, however this lead to specificities of less than 40%. To overcome this, a strategic ML pipeline was devised and three tasks were developed. Random forest achieved the strongest performance overall. High accuracies and sensitivities of 70%, 80% and 70% and specificities of 71%, 76% and 71% were achieved for classifying; (i) no food effect vs food effect, (ii) negative food vs positive food effect and (iii) no food effect vs negative food effect vs positive food effect, respectively. Feature importance using random forest ranked the features by importance for building the predictive tasks. The calculated dose number was the most important feature. Here, ML has provided an effective screening tool for predicting the food effect, with the potential to select lead compounds with no food effect, reduce the number of animal studies, and accelerate oral drug development studies.

Atmospheric Autoxidation of Organophosphate Esters.

Organophosphate esters (OPEs), widely used as flame retardants and plasticizers, have frequently been identified in the atmosphere. However, their atmospheric fate and toxicity associated with atmospheric transformations are unclear. Here, we performed quantum chemical calculations and computational toxicology to investigate the reaction mechanism of peroxy radicals of OPEs (OPEs-RO2•), key intermediates in determining the atmospheric chemistry of OPEs, and the toxicity of the reaction products. TMP-RO2• (R1) and TCPP-RO2• (R2) derived from trimethyl phosphate and tris(2-chloroisopropyl) phosphate, respectively, are selected as model systems. The results indicate that R1 and R2 can follow an H-shift-driven autoxidation mechanism under low NO concentration ([NO]) conditions, clarifying that RO2• from esters can follow an autoxidation mechanism. The unexpected autoxidation mechanism can be attributed to the distinct role of the ─(O)3P(═O) phosphate-ester group in facilitating the H-shift of OPEs-RO2• from commonly encountered ─OC(═O)─ and ─ONO2 ester groups in the atmosphere. Under high [NO] conditions, NO can mediate the autoxidation mechanism to form organonitrates and alkoxy radical-related products. The products from the autoxidation mechanism have low volatility and aquatic toxicity compared to their corresponding parent compounds. The proposed autoxidation mechanism advances our current understanding of the atmospheric RO2• chemistry and the environmental risk of OPEs.

Impact of rhizosphere microorganisms on arsenic (As) transformation and accumulation in a traditional Chinese medical plant.

Panax notoginseng is an important traditional medicinal plant, but the commercial value is threatened by root-rot disease caused by rhizosphere microbes and a potential health risk caused by plant arsenic (As) accumulation. Whether rhizospheric microbes isolated from P. notoginseng rhizosphere soil could impact As uptake and transport into P. notoginseng is not yet known. Among the three root-rot disease-causing pathogens Fusarium flocciferum (PG 1), Fusarium oxysporum (PG 2), and Fusarium solani (PG 3) and one root-rot disease biocontrol fungus Trichoderma koningiopsis (FC 1) and five biocontrol-exerting bacterial species Bacillus siamensis (BC 1), Delftia acidovorans (BC 2), Brevibacillus formosus (BC 3), Mortierella alpine (BC 4), and Bacillus subtilis (BC 5), one As-resistant pathogen and four biocontrol microorganisms with As-resistant ability were identified. The As-transforming ability of the identified fungi and bacteria was ranked in the order of FC 1 > PG 1 and BC 2 > BC 3 > BC 1, respectively. Then, the As-resistant biocontrol and pathogenic microbes were initiated to colonize the rhizosphere of 1-year-old P. notoginseng seedlings growing in artificially As(V)-contaminated soil to evaluate the impact of microbe inoculation on P. notoginseng As uptake and transport capacity. Concentration of As in P. notoginseng tissues decreased in the order of the sequence stem > root > leaf. Compared to treatment without colonization by microorganism, inoculation with microorganisms increased As root uptake efficiency and root As concentration, especially under treatment of inoculation by BC 2 and PG 1 + BC 2. As transport efficiency from root to stem decreased by inoculation with microorganism, especially under treatment with inoculation of BC 2 and PG 1 + BC 2. However, the impact of microorganism colonization on As stem to leaf transport efficiency was not obvious. In summary, inoculation with rhizosphere microbes may increase As accumulation in P. notoginseng root, especially when using bacteria with high As transformation ability. Therefore, it is necessary to evaluate the As transformation capacity before applying biological control microorganism to the rhizosphere of P. notoginseng.