Integrated causal inference modeling uncovers novel causal factors and potential therapeutic targets of Qingjin Yiqi granules for chronic fatigue syndrome

Objective:Chronic fatigue syndrome(CFS)is a prevalent symptom of post-coronavirus disease 2019(COVID-19)and is associated with unclear disease mechanisms.The herbal medicine Qingjin Yiqi granules(QJYQ)constitute a clinically approved formula for treating post-COVID-19;however,its potential as a drug target for treating CFS remains largely unknown.This study aimed to identify novel causal factors for CFS and elucidate the potential targets and pharmacological mechanisms of action of QJYQ in treating CFS.Methods:This prospective cohort analysis included 4,212 adults aged≥65 years who were followed up for 7 years with 435 incident CFS cases.Causal modeling and multivariate logistic regression analysis were performed to identify the potential causal determinants of CFS.A proteome-wide,two-sample Mendelian randomization(MR)analysis was employed to explore the proteins associated with the identified causal factors of CFS,which may serve as potential drug targets.Furthermore,we performed a virtual screening analysis to assess the binding affinity between the bioactive compounds in QJYQ and CFS-associated proteins.Results:Among 4,212 participants(47.5%men)with a median age of 69 years(interquartile range:69–70 years)enrolled in 2004,435 developed CFS by 2011.Causal graph analysis with multivariate logistic regression identified frequent cough(odds ratio:1.74,95%confidence interval[CI]:1.15–2.63)and insomnia(odds ratio:2.59,95%CI:1.77–3.79)as novel causal factors of CFS.Proteome-wide MR analysis revealed that the upregulation of endothelial cell-selective adhesion molecule(ESAM)was causally linked to both chronic cough(odds ratio:1.019,95%CI:1.012–1.026,P=2.75 e^(−05))and insomnia(odds ratio:1.015,95%CI:1.008–1.022,P=4.40 e^(−08))in CFS.The major bioactive compounds of QJYQ,ginsenoside Rb2(docking score:−6.03)and RG4(docking score:−6.15),bound to ESAM with high affinity based on virtual screening.Conclusions:Our integrated analytical framework combining epidemiological,genetic,and in silico data provides a novel strategy for elucidating complex disease mechanisms,such as CFS,and informing models of action of traditional Chinese medicines,such as QJYQ.Further validation in animal models is warranted to confirm the potential pharmacological effects of QJYQ on ESAM and as a treatment for CFS.

Quantifying the impact of earthquakes and geological factors on spatial heterogeneity of debris-flow prone areas:A case study in the Hengduan Mountains

Understanding the spatial heterogeneity of debris-flow-prone areas holds significant implications for regional risk management, particularly in seismically active regions with geological faults. Despite the significance of this knowledge, a comprehensive quantification of the influence of regional topographical and geological factors on the spatial heterogeneity of debris-flow-prone areas has been lacking. This study selected the Hengduan Mountains, an earthquake-prone region characterized by diverse surface conditions and complex landforms, as a representative study area. An improved units zoning and objective factors identification methodology was employed in earthquake and fault analysis to assess the impact of seismic activity and geological factors on spatial heterogeneity of debrisflow prone areas. Results showed that the application of GIS technology with hydrodynamic intensity and geographical units analysis can effectively analyze debris-flow prone areas. Meanwhile, earthquake and fault zones obviously increase the density of debrisflow prone catchments and make them unevenly distributed. The number of debris-flow prone areas shows a nonlinear variation with the gradual increase of geomorphic factor value. Specifically, the area with 1000 m-2500 m elevation difference, 25°-30° average slope, and 0.13-0.15 land use index is the most favorable conditions for debris-flow occurrence;The average annual rainfall from 600 to 1150 mm and landslides gradient from 16° to 35° are the main causal factors to trigger debris flow. Our study sheds light on the quantification of spatial heterogeneity in debris flow-prone areas in earthquake-prone regions, which can offer crucial support for post-debris flow risk management strategies.

Hazards from lakes and reservoirs: new interpretation of the Vaiont disaster

Hazards in reservoirs and lakes arising from subaerial landslides causing impact waves(or ‘lake tsunamis’) are now well known, with several recent examples having been investigated in detail. The potential scale of such hazards was not widely known at the time of the Vaiont dam project in the 1950s and early 1960s, although a small wave triggered by a landslide at another new reservoir nearby in the Dolomites(northern Italy) drew the possible hazard to the attention of the Vaiont project’s managers. The Vaiont disaster in 1963 arose from a combination of disparate and seemingly unrelated factors and circumstances that led to an occurrence that could not have been imagined at that time. The ultimate cause was a very large landslide moving very rapidly into a reservoir and displacing the water. The resulting wave overtopped the dam to a height of around 175 m and around 2000 people were killed. This paper identifies and examines all of the issues surrounding the Vaiont dam and landslide in order to identify causal factors, contributory factors(including aggravating factors) and underlying factors. In doing so, it demonstrates that the disaster arose from the Vaiont dam project and cannot be attributed simply to the landslide. Underlying geological factors gave rise to the high speed of the landslide, which would have occurred anyway at some time. However, without the contributory factors that account for the presence of the reservoir, i.e. the choice of location for the project and management of the project with respect to a possible landslide hazard, there would have been no disaster. Indeed, the disaster could have been avoided if the reservoir could have been emptied pending further ground investigations. Understanding of this case provides many lessons for future dam projects in mountainous locations but also highlights an ongoing and perhaps under-appreciated risk from similar events involving other water bodies including geologically recent lakes formed behind natural landslide dams.

Fine genetic mapping of the chromosome 11q23.3 region in a Han Chinese population:insights into the apolipoprotein genes underlying the blood lipid-lipoprotein variances

The unusual chromosome 11q23.3 harboring the apolipoprotein(APO)gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases.However,its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed.We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing,association analyses,genetic fine mapping,and functional interpretation.The present study identified new meaningful genetic associations that were not simply determined by statistical significance.In addition to the APOA5 gene,we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids.Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses.rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility.Similarly,multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol.Our findings provided novel insights into this genomic locus in the Chinese population.