The lung-gut crosstalk in respiratory and inflammatory bowel disease

Both lung and gut belong to the common mucosal immune system (CMIS), with huge surface areas exposed to the external environment. They are the main defense organs against the invasion of pathogens and play a key role in innate and adaptive immunity. Recently, more and more evidence showed that stimulation of one organ can affect the other, as exemplified by intestinal complications during respiratory disease and vice versa, which is called lung-gut crosstalk. Intestinal microbiota plays an important role in respiratory and intestinal diseases. It is known that intestinal microbial imbalance is related to inflammatory bowel disease (IBD), this imbalance could impact the integrity of the intestinal epithelial barrier and leads to the persistence of inflammation, however, gut microbial disturbances have also been observed in respiratory diseases such as asthma, allergy, chronic obstructive pulmonary disease (COPD), and respiratory infection. It is not fully clarified how these disorders happened. In this review, we summarized the latest examples and possible mechanisms of lung-gut crosstalk in respiratory disease and IBD and discussed the strategy of shaping intestinal flora to treat respiratory diseases

Development and validation of questionnaire-based machine learning models for predicting all-cause mortality in a representative population of China

BackgroundConsidering that the previously developed mortality prediction models have limited applications to the Chinese population, a questionnaire-based prediction model is of great importance for its accuracy and convenience in clinical practice.MethodsTwo national cohort, namely, the China Health and Nutrition Survey (8,355 individual older than 18) and the China Health and Retirement Longitudinal Study (12,711 individuals older than 45) were used for model development and validation. One hundred and fifty-nine variables were compiled to generate predictions. The Cox regression model and six machine learning (ML) models were used to predict all-cause mortality. Finally, a simple questionnaire-based ML prediction model was developed using the best algorithm and validated.ResultsIn the internal validation set, all the ML models performed better than the traditional Cox model in predicting 6-year mortality and the random survival forest (RSF) model performed best. The questionnaire-based ML model, which only included 20 variables, achieved a C-index of 0.86 (95%CI: 0.80–0.92). On external validation, the simple questionnaire-based model achieved a C-index of 0.82 (95%CI: 0.77–0.87), 0.77 (95%CI: 0.75–0.79), and 0.79 (95%CI: 0.77–0.81), respectively, in predicting 2-, 9-, and 11-year mortality.ConclusionsIn this prospective population-based study, a model based on the RSF analysis performed best among all models. Furthermore, there was no significant difference between the prediction performance of the questionnaire-based ML model, which only included 20 variables, and that of the model with all variables (including laboratory variables). The simple questionnaire-based ML prediction model, which needs to be further explored, is of great importance for its accuracy and suitability to the Chinese general population

Effects of elevated atmospheric [CO2] on grain starch characteristics in different specialized wheat

The increasing atmospheric [CO2] poses great challenges to wheat production. Currently, the response of starch characteristics in different specialized wheat cultivars to elevated [CO2], as well as the underlying physiological and molecular mechanisms remains unclear. Therefore, an experiment was conducted with open-top chambers to study the effects of ambient [CO2] [a(CO2)] and elevated [CO2] [e(CO2)] on photosynthetic performance, yield and starch characteristics of bread wheat (Zhengmai 369, ZM369) and biscuit wheat (Yangmai 15, YM15) from 2020 to 2022. The results demonstrated a significant improvement in photosynthetic performance, yield, amylose and amylopectin content, volume ratio of large granules under e[CO2]. Moreover, e[CO2] upregulated the gene expression and enzyme activities of GBSS (Granule-bound starch synthase) and SSS (Soluble starch synthase), increased starch pasting viscosity, gelatinization enthalpy and crystallinity. Compared to YM15, ZM369 exhibited a higher upregulation of GBSSI, greater increase in amylose content and volume ratio of large granules, as well as higher gelatinization enthalpy and crystallinity. However, ZM369 showed a lower increase in amylopectin content and a lower upregulation of SSSI and SSSII. Correlation analysis revealed amylose and amylopectin content had a positive correlation with GBSS and SSS, respectively, a significant positively correlation among the amylose and amylopectin content, starch granule volume, and pasting properties. In conclusion, these changes may enhance the utilization value of biscuit wheat but exhibit an opposite effect on bread wheat. The results provide a basis for selecting suitable wheat cultivars and ensuring food security under future climate change conditions

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

MOLECULAR STRUCTURES AND ELECTRONIC STATES OF SC-TERPHENYL COMPLEXES DETERMINED BY PULSED FIELD IONIZATION-ZERO ELECTRON KINETIC ENERGY PHOTOELECTRON SPECTROSCOPY

Author Institution: Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055Scandium complexes of p- and m-terphenyls were prepared in laser-vaporization supersonic molecular beams and studied by pulsed field ionization-zero electron kinetic energy photoelectron spectroscopy and density functional theory calculations. Several initial structures with Sc binding at different phenyl rings and bridging carbon bonds were considered in the calculations. A structure with the six-fold Sc binding at the terminal ring of these terphenyls was identified in our experiments. In both complexes, the ground electronic state of the neutral complexes was determined to be $^4$A, and that of the corresponding ion was $^3$A. For Sc-(p-terphenyl), the adiabatic ionization energy of 38838(6) cm$^{-1}$ and a ring bending frequency of 49 cm$^{-1}$ was measured for the quartet neutral molecule, and four vibrational frequencies of 354, 309, 77, and 44 cm$^{-1}$ were identified for the triplet ion. These ion frequencies were assigned to two metal-ligand stretches, a ring torsion, and a ring bend, respectively. For Sc-(m-terphenyl), the adiabatic ionization energy was measured to be 38290(6) cm$^{-1}$, and seven ion vibrational frequencies were determined to be 436, 377, 355, 330, 303, 279, and 46 cm$^{-1}$. Similar to the p-terphenyl complex, these ion frequencies were assigned to metal-ligand stretches and ring deformations

PULSED FIELD IONIZATION ELECTRON SPECTROSCOPY OF CYCLOPENTADIENYL DIALUMINUM COMPLEX

Author Institution: Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055The cyclopentadienyl dialuminum complex, (C$_{5}$H$_{5}$)Al$_{2}$, is synthesized in a supersonic molecular beam, where aluminum atoms and dimers are produced by laser vaporization, and cyclopentadienyl radicals are generated from photolysis of cyclopentadiene (C$_{5}$H$_{6}$) molecules. Vibrationally resolved electronic spectra of the complex are measured using pulsed-field ionization zero electron kinetic energy spectroscopy. Three initial conformations are considered for the complex: one with an Al atom binding to each side of the C$_{5}$H$_{5}$ ring and two others with an Al$_{2}$ molecule lying vertically or horizontally on one side of the ligand ring. A structure with the Al$_{2}$ molecule lying vertically on the top of the C$_{5}$H$_{5}$ ring is identified by comparing the spectroscopic measurements to $ab$ $initio$ calculations. The (C$_{5}$H$_{5}$)Al$_{2}$ neutral complex has a $^2$A$^{\prime \prime}$ ground electronic state in Jahn-Teller distorted $C$$_{s}$ symmetry and the corresponding ion has a $^1$A$_1$ ground state in $C$$_{5v}$ symmetry. The ionization energy of (C$_{5}$H$_{5}$)Al$_{2}$ is measured to be 40690(5) cm$^{-1}$. For the cationic $^1$A$_1$ state, the frequencies of the metal-ligand stretching, metal-metal stretching, and metal-ligand bending modes are 482, 175, and 50 cm$^{-1}$, respectively. In addition, a (C$_{5}$H$_{5}$)-Al$_{2}$ bending mode of the neutral $^2$A$^{\prime \prime}$ state is measured to be 26 cm$^{-1}$