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"Pan, Emily"
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The astonishing color of after
After her mother's suicide, grief-stricken Leigh Sanders travels to Taiwan to stay with grandparents she's never met, determined to find her mother--who she believes turned into a bird.
BOOK
Potential effects of low-dose average CT on cardiac implantable electronic devices
BackgroundAverage CT has been shown to be more accurate than conventional helical CT in quantitation of the PET data. The risk of CT irradiation of a cardiac implantable electronic device (CIED) causing an adverse event is low and is generally outweighed by the clinical benefit of a medically indicated examination. However, irradiation of CIED over one breath cycle in cine CT scan for average CT could impose risks on a patient who is pacing dependent. The purpose of this study was to demonstrate that low-dose average CT can be safe for CIED.MethodsA Medtronic CIED of model Protecta VR was submerged in a saline bath for a series of 4-s cine CT scans on a GE CT scanner programmed to deliver a 2-cm-wide radiation at a dose rate of 0.9 to 41.2 mGy/s to the CIED. The number of over-sensings was recorded as the interference of radiation to the CIED.ResultsDose rates ≥ 1.9 mGy/s caused over-sensing. The higher the dose rate, the more over-sensings there were. The lowest dose rate of 0.9 mGy/s did not cause any over-sensing.ConclusionsLow-dose average CT at 0.9 mGy/s can be safe for a CIED patient who is pacing dependent.
Journal Article
Structural bioinformatics studies of six human ABC transporters and their AlphaFold2-predicted water-soluble QTY variants
Human ATP-binding cassette (ABC) transporters are one of the largest families of membrane proteins and perform diverse functions. Many of them are associated with multidrug resistance that often results in cancer treatment with poor outcomes. Here, we present the structural bioinformatics study of six human ABC membrane transporters with experimentally determined cryo-electron microscopy (CryoEM) structures including ABCB7, ABCC8, ABCD1, ABCD4, ABCG1, ABCG5, and their AlphaFold2-predicted water-soluble QTY variants. In the native structures, there are hydrophobic amino acids such as leucine (L), isoleucine (I), valine (V), and phenylalanine (F) in the transmembrane alpha helices. These hydrophobic amino acids are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T), and tyrosine (Y). Therefore, these QTY variants become water soluble. We also present the superposed structures of native ABC transporters and their water-soluble QTY variants. The superposed structures show remarkable similarity with root mean square deviations between 1.064 and 3.413 Å despite significant (41.90–54.33%) changes to the protein sequence of the transmembrane domains. We also show the differences in hydrophobicity patches between the native ABC transporters and their QTY variants. We explain the rationale behind why the QTY membrane protein variants become water soluble. Our structural bioinformatics studies provide insight into the differences between the hydrophobic helices and hydrophilic helices and will likely further stimulate designs of water-soluble multispan transmembrane proteins and other aggregated proteins. The water-soluble ABC transporters may be useful as soluble antigens to generate therapeutic monoclonal antibodies for combating multidrug resistance in clinics.
Journal Article
CrMP-Sol database: classification, bioinformatic analyses and comparison of cancer-related membrane proteins and their water-soluble variant designs
Membrane proteins are critical mediators for tumor progression and present enormous therapeutic potentials. Although gene profiling can identify their cancer-specific signatures, systematic correlations between protein functions and tumor-related mechanisms are still unclear. We present here the CrMP-Sol database (
https://bio-gateway.aigene.org.cn/g/CrMP
), which aims to breach the gap between the two. Machine learning was used to extract key functional descriptions for protein visualization in the 3D-space, where spatial distributions provide function-based predictive connections between proteins and cancer types. CrMP-Sol also presents QTY-enabled water-soluble designs to facilitate native membrane protein studies despite natural hydrophobicity. Five examples with varying transmembrane helices in different categories were used to demonstrate the feasibility. Native and redesigned proteins exhibited highly similar characteristics, predicted structures and binding pockets, and slightly different docking poses against known ligands, although task-specific designs are still required for proteins more susceptible to internal hydrogen bond formations. The database can accelerate therapeutic developments and biotechnological applications of cancer-related membrane proteins.
Journal Article
Early and late outcomes after open ascending aortic surgery: 47-year experience in a single centre
The aims of the study are to describe the long-term survival of patients undergoing primary open ascending aortic surgery and to portray the evolution of aortic surgery during six decades in a single centre. Included were all 614 patients who underwent primary ascending aortic surgery in 1968–2014 at one Nordic university hospital. Patients were identified and data were collected from patient records and surgical logs. Mortality data were acquired from the national registry. Median follow-up was 11.2 years using reverse Kaplan–Meier method. Overall 30-day survival was 91.2% and for 30-day survivor rates were 86.9, 77.6, 52.1, 38.3 and 26.7% at 5, 10, 20, 30 and 40 years. There was no significant difference in long-term survival for 30-day survivors (p = 0.105) between patients treated emergently for dissection/rupture and electively (mainly ascending aortic aneurysms). On Cox regression era of surgery (p = 0.006), increasing age (p < 0.001) and indication (p < 0.001) were predictors of 30-day mortality. Arch involvement indicated twofold risk (HR 2.09, p = 0.05) compared to non-arch involved. Only increasing age (p < 0.001) predicted long-term mortality. There was a sixfold risk of 30-day mortality in the earliest era compared to the latest (p = 0.03). After the early postoperative phase following ascending aortic surgery, the surgical indication and urgency of the index operation have no significant impact on long-term survival. The very long term survival after ascending aortic surgery is excellent for 30-day survivors and improved through the era. Surgical treatment has improved and perioperative mortality has decreased significantly in 47 years.
Journal Article
PRO‐LDM: A Conditional Latent Diffusion Model for Protein Sequence Design and Functional Optimization
The diffusion model has grasped enormous attention in the computer vision field and emerged as a promising algorithm in protein design for precise structure and sequence generation. Here PRO‐LDM is introduced: a modular multi‐tasking framework combining design fidelity and computational efficiency, by integrating the diffusion model in latent space. The model learns biological representations at local and global levels, to design natural‐like species with enhanced diversity, or optimize protein properties and functions. Its modular nature also enables the integration with alternative pre‐trained encoders for enhanced generalization capability. Outlier design can be implemented by adjusting the classifier‐free guidance that enables PRO‐LDM to sample vastly different regions in the latent space. The approach is demonstrated in generating a novel green‐fluorescence‐protein variant with notably enhanced fluorescence in multiple working scenarios along with increased solubility and stability. The model provides a versatile tool to effectively extract physicochemical and evolutionary information in sequences for designing new proteins with optimized performances. PRO‐LDM is a modular latent diffusion framework that learns hierarchical biological representations to enable efficient and high‐fidelity protein design. PRO‐LDM can design species that resemble natural sequences with enhanced diversity or optimize protein functions. It demonstrates strong performance in designing functional GFP variants with enhanced fluorescence and stability.
Journal Article
Impact of national holidays and weekends on incidence of acute type A aortic dissection repair
Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54–0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68–0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days.
Journal Article
Structure Bioinformatics of Six Human Integral Transmembrane Enzymes and their AlphaFold3 Predicted Water-Soluble QTY Analogs: Insights into FACE1 and STEA4 Binding Mechanisms
Objective
Human integral membrane enzymes are essential for catalyzing a wide range of biochemical reactions and regulating key cellular processes. However, studying these enzymes remains challenging due to their hydrophobic nature, which necessitates the use of detergents. This study explores whether applying the QTY code can reduce the hydrophobicity of these enzymes while preserving their structures and functions, thus facilitating bioinformatics analysis of six key integral membrane enzymes: MGST2, LTC4S, PTGES, FACE1, STEA4, and SCD.
Methods
The water-soluble QTY analogs of the six membrane enzymes were predicted using AlphaFold3. The predicted structures were superposed with CyroEM determined native structures in PyMOL to observe changes in structure and protein-ligand binding ability.
Results
The native membrane enzymes superposed well with their respective QTY analogs, with the root mean square deviation (RMSD) ranging from 0.273 Å to 0.875 Å. Surface hydrophobic patches on the QTY analogs were significantly reduced. Importantly, the protein-ligand interactions in FACE1 and STEA4 were largely preserved, indicating maintained functionality.
Conclusion
Our structural bioinformatics studies using the QTY code and AlphaFold3 not only provide the opportunities of designing more water-soluble integral membrane enzymes, but also use these water-soluble QTY analogs as antigens for therapeutic monoclonal antibody discovery to specifically target the key integral membrane enzymes.
Journal Article
Temperature effects on incidence of surgery for acute type A aortic dissection in the Nordics
We aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (≤−5°C) and hot temperatures (≥21°C) compared to optimal temperature were 1.47 (95% CI: 0.72-2.99) and 1.43 (95% CI: 0.67-3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association.
Journal Article
Structural Bioinformatics Studies of Integral Transmembrane Enzymes pMMO Complex, C560, CYB, and DHSD and their AlphaFold3-Predicted Water-Soluble QTY Variants
The QTY (glutamine, threonine, tyrosine) code is a simple protein engineering and design tool that systematically replaces the hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) into the hydrophilic amino acids glutamine (Q), threonine (T), and tyrosine (Y), respectively, to enable the water-solubility of membrane proteins including membrane enzymes. In this study, we present the structural bioinformatics study of six membrane protein enzymes with experimentally determined CryoEM structures including the methane monooxygenase pMMO complex (pMOA, pMOB, pMOC), CYB, C560, DHSD, and their AlphaFold3-predicted water-soluble QTY variants. We applied the QTY code only to the transmembrane alpha-helices of the proteins. We then superposed structures of CryoEM-determined native proteins with their water-soluble QTY variants. The QTY code engineered water-soluble QTY variants demonstrate remarkable structural similarity with their native structures, with RMSD (
oot
ean
quare
eviation) values between 0.506Å and 0.887Å despite significant (33.33–86.61%) changes to the protein sequence of the transmembrane domains. To verify the effectiveness of our study, we show the changes in hydrophobicity surfaces between the native proteins and their QTY variants, and explain the rationale behind such change. Our structural bioinformatics studies provide key insight into differences between the hydrophobic alpha-helices and alpha-hydrophilic helices. The QTY code will likely further aid the future applications of methane oxidation enzymes. The water-soluble QTY variants could aid in studying and utilization of the enzymes in aqueous environments without detergent solubilization and stabilization. These QTY variant membrane enzymes may be particularly useful for future industrial-scale production in aqueous chassis such as filamentous algae.
Journal Article