229 research outputs found
Atom-Specific Modification of Uracil Bases with Selenium for RNA Structure and Function Studies
The atom-specific modification has been extensively applied in RNA function and structure investigations, catalysis analysis, mechanism studies, as well as therapeutics discoveries. Selenium-modified uridine (SeU-RNA) is one of the naturally occurring modifications that was discovered in bacterial tRNAs (SeU-RNA) at the wobble position of the anticodon loop. Its exact role in the RNA-RNA interaction, especially during the mRNA decoding is not completely understood but it was proposed that such Se derivatization on tRNAs probably improves the accuracy and efficiency of base-pairing. The wobble base pairs, where U in RNA (or T in DNA) pairs with G instead of A, might compromise the high specificity of the base pairing. The U/G wobble pairing is ubiquitous in RNA, especially in non-coding RNA. To assist the research exploration, we have hypothesized to discriminate against U/G wobble pair by tailoring the steric and electronic effects at the 2-exo position of uridine base and replacing 2-exo oxygen with a selenium atom. This oxygen replacement with selenium offers a unique chemical strategy to enhance the base pairing specificity at the atomic level. Here, we report the first synthesis of the 2-Se-U-RNAs through synthetic incorporation of 2-Se-uridine (SeU) phosphoramidite as well as enzymatic incorporation of 2-Se-uridine triphosphate. Our biophysical and structural studies of the SeU-RNAs indicate that this single atom replacement can indeed create a novel U/A base pair with higher specificity than the natural one. We reveal that the SeU/A pair maintains a structure virtually identical to the native U/A base pair, while discriminating against U/G wobble pair. Moreover, we have demonstrated that the synthesized SeUTPs (2-Se-UTP and 4-Se-UTP) are stable and recognizable by T7 RNA polymerase. Furthermore, the transcribed SeU-hammerhead ribozyme has the similar activity as the corresponding native, which suggests usefulness of SeU-RNAs in function and structure studies of noncoding RNAs, including the Se-tRNAs
Does Misclassifying Non-confounding Covariates as Confounders Affect the Causal Inference within the Potential Outcomes Framework?
The Potential Outcome Framework (POF) plays a prominent role in the field of
causal inference. Most causal inference models based on the POF (CIMs-POF) are
designed for eliminating confounding bias and default to an underlying
assumption of Confounding Covariates. This assumption posits that the
covariates consist solely of confounders. However, the assumption of
Confounding Covariates is challenging to maintain in practice, particularly
when dealing with high-dimensional covariates. While certain methods have been
proposed to differentiate the distinct components of covariates prior to
conducting causal inference, the consequences of treating non-confounding
covariates as confounders remain unclear. This ambiguity poses a potential risk
when conducting causal inference in practical scenarios. In this paper, we
present a unified graphical framework for the CIMs-POF, which greatly enhances
the comprehension of these models' underlying principles. Using this graphical
framework, we quantitatively analyze the extent to which the inference
performance of CIMs-POF is influenced when incorporating various types of
non-confounding covariates, such as instrumental variables, mediators,
colliders, and adjustment variables. The key findings are: in the task of
eliminating confounding bias, the optimal scenario is for the covariates to
exclusively encompass confounders; in the subsequent task of inferring
counterfactual outcomes, the adjustment variables contribute to more accurate
inferences. Furthermore, extensive experiments conducted on synthetic datasets
consistently validate these theoretical conclusions.Comment: 12 pages, 4 figure
Warburg Effects in Cancer and Normal Proliferating Cells: Two Tales of the Same Name
It has been observed that both cancer tissue cells and normal proliferating cells (NPCs) have the Warburg effect. Our goal here is to demonstrate that they do this for different reasons. To accomplish this, we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO. Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect, to raise the intracellular pH from ∼6.8 to ∼7.2 and to prepare for cell division energetically. Once cell cycle starts, the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release, to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral. The cells go back to the normal respiration-based ATP production once the cell division phase ends. In comparison, cancer cells have reached their intracellular pH at ∼7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed. Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters. Co-expression analyses suggest that lactic acid secretion is regulated by external, non-pH related signals. Overall, our data strongly suggest that the two cell types have the Warburg effect for very different reasons
VLUCI: Variational Learning of Unobserved Confounders for Counterfactual Inference
Causal inference plays a vital role in diverse domains like epidemiology,
healthcare, and economics. De-confounding and counterfactual prediction in
observational data has emerged as a prominent concern in causal inference
research. While existing models tackle observed confounders, the presence of
unobserved confounders remains a significant challenge, distorting causal
inference and impacting counterfactual outcome accuracy. To address this, we
propose a novel variational learning model of unobserved confounders for
counterfactual inference (VLUCI), which generates the posterior distribution of
unobserved confounders. VLUCI relaxes the unconfoundedness assumption often
overlooked by most causal inference methods. By disentangling observed and
unobserved confounders, VLUCI constructs a doubly variational inference model
to approximate the distribution of unobserved confounders, which are used for
inferring more accurate counterfactual outcomes. Extensive experiments on
synthetic and semi-synthetic datasets demonstrate VLUCI's superior performance
in inferring unobserved confounders. It is compatible with state-of-the-art
counterfactual inference models, significantly improving inference accuracy at
both group and individual levels. Additionally, VLUCI provides confidence
intervals for counterfactual outcomes, aiding decision-making in risk-sensitive
domains. We further clarify the considerations when applying VLUCI to cases
where unobserved confounders don't strictly conform to our model assumptions
using the public IHDP dataset as an example, highlighting the practical
advantages of VLUCI.Comment: 15 pages, 8 figure
Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy
Cardiomyopathies are a clinically heterogeneous group of cardiac diseases characterized by heart muscle damage, resulting in myocardium disorders, diminished cardiac function, heart failure, and even sudden cardiac death. The molecular mechanisms underlying the damage to cardiomyocytes remain unclear. Emerging studies have demonstrated that ferroptosis, an iron-dependent non-apoptotic regulated form of cell death characterized by iron dyshomeostasis and lipid peroxidation, contributes to the development of ischemic cardiomyopathy, diabetic cardiomyopathy, doxorubicin-induced cardiomyopathy, and septic cardiomyopathy. Numerous compounds have exerted potential therapeutic effects on cardiomyopathies by inhibiting ferroptosis. In this review, we summarize the core mechanism by which ferroptosis leads to the development of these cardiomyopathies. We emphasize the emerging types of therapeutic compounds that can inhibit ferroptosis and delineate their beneficial effects in treating cardiomyopathies. This review suggests that inhibiting ferroptosis pharmacologically may be a potential therapeutic strategy for cardiomyopathy treatment
De-confounding Representation Learning for Counterfactual Inference on Continuous Treatment via Generative Adversarial Network
Counterfactual inference for continuous rather than binary treatment
variables is more common in real-world causal inference tasks. While there are
already some sample reweighting methods based on Marginal Structural Model for
eliminating the confounding bias, they generally focus on removing the
treatment's linear dependence on confounders and rely on the accuracy of the
assumed parametric models, which are usually unverifiable. In this paper, we
propose a de-confounding representation learning (DRL) framework for
counterfactual outcome estimation of continuous treatment by generating the
representations of covariates disentangled with the treatment variables. The
DRL is a non-parametric model that eliminates both linear and nonlinear
dependence between treatment and covariates. Specifically, we train the
correlations between the de-confounded representations and the treatment
variables against the correlations between the covariate representations and
the treatment variables to eliminate confounding bias. Further, a
counterfactual inference network is embedded into the framework to make the
learned representations serve both de-confounding and trusted inference.
Extensive experiments on synthetic datasets show that the DRL model performs
superiorly in learning de-confounding representations and outperforms
state-of-the-art counterfactual inference models for continuous treatment
variables. In addition, we apply the DRL model to a real-world medical dataset
MIMIC and demonstrate a detailed causal relationship between red cell width
distribution and mortality.Comment: 15 pages,4 figure
2-Selenouridine Triphosphate Synthesis and Se-RNA Transcription
2-Selenouridine (SeU) is one of the naturally occurring modifications of Se-tRNAs (SeU-RNA) at the wobble position of the anticodon loop. Its role in the RNA-RNA interaction, especially during the mRNA decoding, is elusive. To assist the research exploration, herein we report the enzymatic synthesis of the SeU-RNA via 2-selenouridine triphosphate (SeUTP) synthesis and RNA transcription. Moreover, we have demonstrated that the synthesized SeUTP is stable and recognizable by T7 RNA polymerase. Under the optimized conditions, the transcription yield of SeU-RNA can reach up to 85% of the corresponding native RNA. Furthermore, the transcribed SeU-hammerhead ribozyme has the similar activity as the corresponding native, which suggests usefulness of SeU-RNAs in function and structure studies of noncoding RNAs, including the Se-tRNAs
Microneedle interventional therapy combined with cervical spine manipulation for cervicogenic dizziness
Metabolic profile, bioavailability and toxicokinetics of zearalenone-14-glucoside in rats after oral and intravenous administration by liquid chromatography high-resolution mass spectrometry and tandem mass spectrometry
Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. The plasma concentrations of ZEN-14G and its major five metabolites were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The data were analyzed via non-compartmental analysis using software WinNonlin 6.3. The results indicated that ZEN-14G was rapidly hydrolyzed into ZEN in vivo. In addition, the major parameters of ZEN-14G following intravenous administration were: area under the plasma concentration-time curve (AUC), 1.80 h.ng/mL; the apparent volume of distribution (V-Z), 7.25 L/kg; and total body clearance (CL), 5.02 mL/h/kg, respectively. After oral administration, the typical parameters were: AUC, 0.16 h.ng/mL; V-Z, 6.24 mL/kg; and CL, 4.50 mL/h/kg, respectively. The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism. Therefore, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was adopted to clarify the metabolic profile of ZEN-14G in rats' plasma. As a result, eight metabolites were identified in which ZEN-14-glucuronic acid (ZEN-14GlcA) had a large yield from the first time-point and continued accumulating after oral administration, indicating that ZEN-14-glucuronic acid could serve a potential biomarker of ZEN-14G. The obtained outcomes would prompt the accurate safety evaluation of ZEN-14G
ECPC-IDS:A benchmark endometrail cancer PET/CT image dataset for evaluation of semantic segmentation and detection of hypermetabolic regions
Endometrial cancer is one of the most common tumors in the female
reproductive system and is the third most common gynecological malignancy that
causes death after ovarian and cervical cancer. Early diagnosis can
significantly improve the 5-year survival rate of patients. With the
development of artificial intelligence, computer-assisted diagnosis plays an
increasingly important role in improving the accuracy and objectivity of
diagnosis, as well as reducing the workload of doctors. However, the absence of
publicly available endometrial cancer image datasets restricts the application
of computer-assisted diagnostic techniques.In this paper, a publicly available
Endometrial Cancer PET/CT Image Dataset for Evaluation of Semantic Segmentation
and Detection of Hypermetabolic Regions (ECPC-IDS) are published. Specifically,
the segmentation section includes PET and CT images, with a total of 7159
images in multiple formats. In order to prove the effectiveness of segmentation
methods on ECPC-IDS, five classical deep learning semantic segmentation methods
are selected to test the image segmentation task. The object detection section
also includes PET and CT images, with a total of 3579 images and XML files with
annotation information. Six deep learning methods are selected for experiments
on the detection task.This study conduct extensive experiments using deep
learning-based semantic segmentation and object detection methods to
demonstrate the differences between various methods on ECPC-IDS. As far as we
know, this is the first publicly available dataset of endometrial cancer with a
large number of multiple images, including a large amount of information
required for image and target detection. ECPC-IDS can aid researchers in
exploring new algorithms to enhance computer-assisted technology, benefiting
both clinical doctors and patients greatly.Comment: 14 pages,6 figure
- …