Inflammatory bowel disease (IBD) has been reported to be associated with hepatobiliary diseases. Previous observational and Mendelian randomization (MR) studies have suggested a causal association ...between IBD and primary sclerosing cholangitis (PSC). However, it is unclear whether IBD has a causal association with primary biliary cholangitis (PBC): another autoimmune liver disease. We obtained genome-wide association study (GWAS) statistics from published GWASs for PBC, UC, and CD. We screened qualified instrumental variables (IVs) based on the three major assumptions of MR. To determine the causal relationships between UC or CD and PBC, two-sample MR analyses were performed using inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods, and sensitivity analyses were conducted to validate the robustness of the results. We also conducted reverse MR analysis to reveal the causal association between PBC and UC or CD. UC was associated with a higher risk of PBC (OR 1.35, 95% CI 1.05-1.73, P = 0.02) in the IVW method, and CD was associated with an increased risk of PBC (OR 1.18, 95% CI 1.03-1.36, P = 0.02) in IVW. The weighted median and MR-Egger regression of both diseases showed a consistent direction but were not statistically significant. Results of the reverse MR analysis did not suggest genetic susceptibility that PBC was associated with an increased risk of UC (OR 1.05, 95% CI 0.95-1.17, P = 0.34) or CD (OR 1.1, 95% CI 0.99-1.20, P = 0.06). The present study revealed that IBD subtypes could increase the incidence of PBC, but in turn, PBC did not increase the incidence of IBD subtypes. Understanding that IBD and PBC constitute mutual risk factors can help with the clinical management of both diseases.
Because of the strong relationship between the desired molecular activity and its structural core, the screening of focused, core-sharing chemical libraries is a key step in lead optimization. ...Despite the plethora of current research focused on
methods for molecule generation, to our knowledge, no tool capable of designing such libraries has been proposed. In this work, we present a novel tool for
drug design called LibINVENT. It is capable of rapidly proposing chemical libraries of compounds sharing the same core while maximizing a range of desirable properties. To further help the process of designing focused libraries, the user can list specific chemical reactions that can be used for the library creation. LibINVENT is therefore a flexible tool for generating virtual chemical libraries for lead optimization in a broad range of scenarios. Additionally, the shared core ensures that the compounds in the library are similar, possess desirable properties, and can also be synthesized under the same or similar conditions. The LibINVENT code is freely available in our public repository at https://github.com/MolecularAI/Lib-INVENT. The code necessary for data preprocessing is further available at: https://github.com/MolecularAI/Lib-INVENT-dataset.
Epidemiological evidence relating sleep disorders to end-stage renal disease (ESRD) has been obscure. The present study is sought to examine the association between sleep traits and ESRD.
For this ...analysis, we selected genetic instruments for sleep traits from published genome-wide association studies (GWAS). As instrumental variables, independent genetic variations linked with seven sleep-related features (sleep duration, getting up in the morning, daytime napping, chronotype of morning/evening person, sleeplessness/insomnia, non-snoring, and daytime dozing) were chosen. A two-sample Mendelian randomization (TSMR) study was conducted to assess the causal relationship between sleep traits and ESRD (N = 33,061). The reverse MR analysis subsequently determined the causal relationship between ESRD and sleep traits. The causal effects were estimated using inverse variance weighted, MR-Egger, weighted median. To conduct sensitivity studies, Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plot were used. To study the potential mediators, multivariable mendelian randomization analyses were undertaken further.
Genetically predicted sleeplessness/ insomnia (OR = 6.11, 95%CI 1.00-37.3, P = 0.049, FDR = 0.105), getting up in the morning easily(OR = 0.23, 95%CI 0.063-0.85; P = 0.0278, FDR = 0.105), non-snoring (OR = 4.76E-02, 95%CI 2.29E-03-0.985, P = 0.0488, FDR = 0.105) was suggestively associated with the risk of ESRD. However, we found no evidence favoring a causal association between other sleep traits and ESRD through the IVW method.
The present TSMR found no strong evidence of a bidirectional causal association between genetically predicted sleep traits and ESRD.
Slow strain rate tensile test in a hydrogen-rich environment was performed to study the effects of laser peening (LP) on the tensile properties and martensitic transformation of AISI 316L stainless ...steel. Underlying physio-chemical processes involved in hydrogen embrittlement of 316L steel in the hydrogen-rich environment has been proposed. Results show that the grain refinement, mechanical twins and high-density dislocations were found in the laser peened specimens. The movement of hydrogen-carrying dislocations and martensite transformation were prevented by complex grain boundaries and high-density dislocations during tensile process. The ultimate tensile strength of the laser peened specimen were increased by 7.73% and 8.45% in air and hydrogen-rich environment respectively compared with that of non-laser peened specimen. What's more, the elongation loss of laser peened sample was far less than that of non-LP sample in a hydrogen-rich environment. LP induced compressive residual stress (CRS), grain refinement, high-density dislocations and a dense surface layer on the treated surface are beneficial for suppressing hydrogen penetration.
•Tensile properties of 316L steel were improved by LP in the hydrogen-rich environment.•LP was effective for preventing martensitic transformation in 316L steel.•A dynamic hydrogen charging device was developed for tensile test in the hydrogen-rich environment.•Underlying physio-chemical processes involved in HE of 316L steel in the hydrogen-rich environment has been proposed.
Understanding cellular organization demands the best possible spatial resolution in all three dimensions. In fluorescence microscopy, this is achieved by 4Pi nanoscopy methods that combine the ...concepts of using two opposing objectives for optimal diffraction-limited 3D resolution with switching fluorescent molecules between bright and dark states to break the diffraction limit. However, optical aberrations have limited these nanoscopes to thin samples and prevented their application in thick specimens. Here we have developed an improved iso-stimulated emission depletion nanoscope, which uses an advanced adaptive optics strategy to achieve sub-50-nm isotropic resolution of structures such as neuronal synapses and ring canals previously inaccessible in tissue. The adaptive optics scheme presented in this work is generally applicable to any microscope with a similar beam path geometry involving two opposing objectives to optimize resolution when imaging deep in aberrating specimens.
Background
Alzheimer's disease (AD) has become a common illness affecting the elderly, adding to society's social and financial burden. We used two‐sample Mendelian randomization (MR) in this study ...to determine the association between working status and AD.
Methods
We performed a two‐sample MR analysis. The genetic associations were derived from the UK Biobank (n = 263,615) and the International Genomics of Alzheimer's Project (n = 63,926). Inverse variance weighted (IVW), MR‐Egger, and weighted median were used in the MR analysis. The funnel plot, Cochran's Q test, MR‐Egger intercept test, and leave‐one‐out analysis were used in sensitivity analyses. Further risk factor analyses were carried out to look into the potential mediators.
Results
Jobs involve heavy manual or physical work (OR = 2.13, 95%CI 1.36–3.36; p = .0011), job involves mainly walking or standing (OR = 1.74, 95%CI 1.19–2.54; p = .004), and job involves shift work (OR = 2.78, 95%CI 1.14–6.80; p = .02) increased the risk of AD in the IVW analysis. There was no heterogeneity and no horizontal pleiotropy in the sensitivity analysis. Risk factor analysis suggested that each of the above association may be mediated by different risk factors.
Conclusion
Our study adds to the evidence that the development of AD is associated with the working status (job involves heavy manual or physical work, job involves mainly walking or standing, and job involves shift work) by using extensive human genetic data.
This investigation attempts to rationalize various near-neutral pH corrosion fatigue (CF) failure scenarios found during pipeline operations, which continues to be a major consideration in pipeline ...integrity. The phenomenon is often referred to as stress corrosion cracking (SCC) but as will be discussed is more properly considered as CF. Existing CF (SCC) models predict a service life of more than 100years for gas pipelines, as compared with the 20–30years typically seen in the field when these mechanisms are operative. It has been identified from analyzing pressure fluctuations recorded in the field that the underload-type variable amplitude loading schemes often found within 30km downstream of a compressor station are the most prone to crack growth, and these locations comprise more than 70% of all-service and hydrostatic-test failures attributed to stress cracking. In this investigation, underload-type variable amplitude loading schemes were designed and used for crack growth measurements in pipeline steel in near-neutral pH environments. Crack growth enhancement by a factor of 10 was found under the underload-type variable amplitude cyclic loading, as compared with the constant amplitude cyclic loading. There also exist two distinct regimes of crack growth behavior over the range of loading frequency from 5.0×10−1Hz to 10−5Hz under such variable amplitude fatigue. Crack growth rate was found to increase with decreasing loading frequency down to 10−3Hz, while it remained constant below 10−3Hz. This critical loading frequency was successfully modeled based on the crack growth mechanisms identified. The outcome of the investigation agrees well with the failures experienced in the field.
Quantitative phase imaging and measurement of surface topography and fluid dynamics for objects, especially for moving objects, is critical in various fields. Although effective, existing synchronous ...phase-shifting methods may introduce additional phase changes in the light field due to differences in optical paths or need specific optics to implement synchronous phase-shifting, such as the beamsplitter with additional anti-reflective coating and a micro-polarizer array. Therefore, we propose a synchronous phase-shifting method based on the Mach-Zehnder interferometer to tackle these issues in existing methods. The proposed method uses common optics to simultaneously acquire four phase-shifted digital holograms with equal optical paths for object and reference waves. Therefore, it can be used to reconstruct the phase distribution of static and dynamic objects with high precision and high resolution. In the experiment, the theoretical resolution of the proposed system was 1.064 µm while the actual resolution could achieve 1.381 µm, which was confirmed by measuring a phase-only resolution chart. Besides, the dynamic phase imaging of a moving standard object was completed to verify the proposed system's effectiveness. The experimental results show that our proposed method is suitable and promising in dynamic phase imaging and measurement of moving objects using phase-shifting digital holography.
Inflammatory bowel disease (IBD) has been associated with lipid-lowering drugs in observational studies. Drug-target Mendelian randomization (MR) was utilized in this study to examine the causal ...relationship between lipid-lowering drugs and incidence of IBD, aiming to identify new preventive uses for the drugs.
We identified instrumental variables for three classes of lipid-lowering drugs: HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors, using data from the Global Lipids Genetics Consortium. Summary statistics of IBD were obtained from UK Inflammatory Bowel Disease Genetics. The summary-data-based MR (SMR) and the inverse-variance weighted (IVW) MR were used for analysis. Sensitivity analyses were performed by conventional MR methods.
The SMR analysis showed no significant genetic association between increased gene expression of HMGCR, PCSK9, and NPC1L1 and IBD, Crohn's disease (CD) and ulcerative colitis (UC). According to IVW-MR analysis, increased HMGCR expression is associated with a reduced risk of IBD (OR = 0.73, 95% confidence interval (CI) 0.59-0.90, P = 0.003) and CD (OR = 0.75, 95% CI 0.57-0.97, P = 0.03), but not with UC. Additionally, increased NPC1L1 gene expression was associated with elevated risk of IBD (OR = 1.60, 95% CI 1.07-2.40, P = 0.023), but not with CD and UC. However, no significant causal relationships were found between PCSK9 gene expression and IBD, CD, and UC. The sensitivity analysis demonstrated no evidence of heterogeneity or pleiotropy among the reported results.
The heightened expression of genetic variations in HMGCR inhibitor targets could potentially reduce the risk of IBD and CD, while genetic variation in the expression of NPC1L1 targets was positively associated with IBD.
Nanoscale spatiotemporal clustering of RNA polymerase II (Pol II) plays an important role in transcription regulation. However, dynamics of individual Pol II clusters in live-cell nuclei has not been ...measured directly, prohibiting in-depth understanding of their working mechanisms. In this work, we studied the dynamics of Pol II clustering using Bayesian nanoscopy in live mammalian cell nuclei. With 50 nm spatial resolution and 4 s temporal resolution, Bayesian nanoscopy allows direct observation of the assembly and disassembly dynamics of individual Pol II clusters. The results not only provide quantifications of Pol II clusters but also shed light on the understanding of cluster formation and regulation. Our study suggests that transcription factories form on-demand and recruit Pol II molecules in their pre-elongation phase. The assembly and disassembly of individual Pol II clusters take place asynchronously. Overall, the methods developed herein are also applicable to studying a wide realm of real-time nanometer-scale nuclear processes in live cells.
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