Miracle-dz/UniFAR-FTUs huggingface dataset:
JUN mRNA translation regulation is mediated by multiple 5’ UTR and start codon features

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of the JUN mRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of the JUN mRNA by interacting with a stem loop in the 5′ untranslated region (5′ UTR) and with the 5′ -7-methylguanosine cap structure. In addition to its interaction site with eIF3, the JUN 5′ UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity of JUN mRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in the JUN 5′ UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, in JUN regulation. We show that enhancing the interaction of eIF4A with JUN by using the compound Rocaglamide A (RocA) represses JUN translation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute to JUN translation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation for JUN translation and show the potential of JUN as a model transcript for understanding multiple interacting modes of translation regulation.
Gynura segetum induces hepatic sinusoidal obstruction syndrome in a child: A case report

Rationale: Hepatic sinusoidal obstruction syndrome (HSOS), which includes hepatic stasis and portal hypertension, is a rare vascular disorder of the liver. It is often associated with hematopoietic stem cell transplantation. It is also possible to treat this disease using Chinese herbal medicines that contain pyrrolizidine alkaloids (PAs). This disease is extremely rare in children and poses a serious threat to their health. To our knowledge, this is the first case of HSOS in a child with PAs. Patient concerns: We report a 4-year-old boy suffering from abdominal pain, hepatomegaly, massive ascites, elevated liver enzyme level, and severe portal hypertension as a result of the consumption of Gynura segetum (also known as Tusanqi in Chinese, a traditional herbal medicine containing PAs). Diagnoses: The child was finally diagnosed with PA-HSOS based on pathological diagnosis and imaging examination. Intervention: With active symptomatic and supportive care and sequential anticoagulation therapy, the abdominal distension and liver function improved in the patient. Outcomes: The patient was eventually recovered. The levels of liver enzymes, hemoglobin, and bilirubin were normal, and the international normalized ratio fluctuated between 2.0 and 3.0 during 1-year follow-up after discharge. Lessons: This case report emphasizes the prevention of Chinese herb-induced liver injury in children and the importance of active long-term sequential anticoagulant therapy to reduce the progressive damage of PA-HSOS in the liver.
Prediction of severity of dengue infection in children based on hepatic involvement

Abstract Background and Aim To assess the spectrum of hepatic involvement in children with dengue fever (DF) and prediction of severity of dengue infection by early detection of elevated liver enzymes. Methods This prospective observational study was conducted at a tertiary care hospital from June 2019 to September 2019. Children admitted with DF were included. Severity of DF was graded as dengue without warning sign (DNWS), with warning sign (DWS), and severe dengue fever (SDF) according to WHO criteria. Liver injury (LI) was defined as alanine aminotransferase (ALT) more than upper limit of normal irrespective of sex. Results Of 190 children (male, 109) with DF, 60 had DNWS, 49 had DWS, and 81 had SDF. A total of 100 children (52.6%) had LI. The distribution of hepatic involvement spectrum involves hepatomegaly (26.3%), hepatic tenderness (25.2%), features of acute liver failure (1.5%), raised level of ALT (52.6%), raised level of aspartateaminotransferase (AST) (65.8%), prolonged prothrombin time (7.3%), and reduced level of serum albumin (44.7%) in children. Of them, 5.8% and 6.8% of children had >tenfold increase in ALT and AST values. The degree of liver function derangement significantly (P < 0.05) increased with DF severity. In our study, ALT at 422 IU/L (10 times upper limit of normal [ULN]) and AST 689 IU/L (17 times ULN) had similar sensitivity and specificity as WHO recommended cutoff of 1000 IU/L (25 times of ULN) to detect SDF. Conclusion ALT ≥10 times and AST ≥17 times of ULN are as sensitive as ≥25 times (as recommended by WHO) to detect SDF.
Enhancer-MDLF: a novel deep learning framework for identifying cell-specific enhancers

Abstract Enhancers, noncoding DNA fragments, play a pivotal role in gene regulation, facilitating gene transcription. Identifying enhancers is crucial for understanding genomic regulatory mechanisms, pinpointing key elements and investigating networks governing gene expression and disease-related mechanisms. Existing enhancer identification methods exhibit limitations, prompting the development of our novel multi-input deep learning framework, termed Enhancer-MDLF. Experimental results illustrate that Enhancer-MDLF outperforms the previous method, Enhancer-IF, across eight distinct human cell lines and exhibits superior performance on generic enhancer datasets and enhancer–promoter datasets, affirming the robustness of Enhancer-MDLF. Additionally, we introduce transfer learning to provide an effective and potential solution to address the prediction challenges posed by enhancer specificity. Furthermore, we utilize model interpretation to identify transcription factor binding site motifs that may be associated with enhancer regions, with important implications for facilitating the study of enhancer regulatory mechanisms. The source code is openly accessible at https://github.com/HaoWuLab-Bioinformatics/Enhancer-MDLF.
Association of rs5051 and rs699 polymorphisms in angiotensinogen with coronary artery disease in Iranian population: A case-control study

Coronary artery disease (CAD) is the third most common cause of mortality globally (with 17.8 million deaths annually). Angiotensinogen (AGT) and polymorphisms in this gene can be considered as susceptibility factors for CAD. We performed a retrospective case-control study to determine the correlation of AGT rs5051 and rs699 polymorphisms with CAD in an Iranian population. We genotyped 310 CAD patients and 310 healthy subjects using polymerase chain reaction-based methods. To confirm the accuracy of the screening approach, 10% of genotyped subjects were validated using gold-standard Sanger Sequencing. To evaluate the effect of the candidate polymorphisms, white blood cells were randomly purified from the subjects and AGT expression was measured by quantitative reverse transcriptase-polymerase chain reaction. Sex stratification indicated a significant correlation between CAD and male sex (P = .0101). We found a significant association between the rs5051 A allele (P = .002) and the rs699 C allele, and CAD (P = .0122) in recessive and dominant models. Moreover, our findings showed a significant association of the haplotype, including the rs5051 A/A and rs699 T/C genotypes, with CAD (P = .0405). Finally, AGT mRNA levels were significantly decreased in patients harboring the candidate polymorphisms (P = .03). According to our findings The AGT rs5051 A and AGT rs699 C alleles are predisposing variants of CAD risk and severity in the Iranian population.
Impact of Covid -19 incidence rate and government-initiated risk communication measures on individual’s NPI practices

Background Non-pharmaceutical interventions (NPI) are the most widely recognized public health measures recognized globally to prevent the spread of Covid-19. NPIs’ effectiveness may depend on the type, combination of applied interventions, and the level of proper public compliance with the NPIs. The expected outcome of behavioural practices varies relative to the intervention duration. Objectives This study aimed to assess the trend of community compliance to NPI with Covid-19 incidence and government-initiated interventions, and its variation by residence and sociodemographic characteristics of people. Methods A weekly non-participatory field survey on individuals’ NPI practices was observed from the 41st epidemiological week of October 5th, 2020, to the 26th epidemiological week of July 4th, 2021, a total of 39 weeks. The survey covered all 14 regional and national capital cities in Ethiopia. Data collection for the three NPI behaviours (i.e., respiratory hygiene, hand hygiene, and physical distance) was managed weekly at eight public service locations using the Open Data Kit (ODK) tool. The Covid– 19 incidence data and public health measures information from August 3rd, 2020 to July 4th, 2021 were obtained from the Ethiopian Public Health Institute (EPHI). Results More than 180,000 individuals were observed for their NPI practice, with an average of 5,000 observations in a week. About 43% of the observations were made in Addis Ababa, 56% were male and 75% were middle age group (18–50 years). The overall level of NPI compliance was high at the beginning of the observation then peaked around the 13th– 15th epidemiological weeks then declined during the rest of the weeks. The peak NPI compliance periods followed the high Covid-19 death incidence and government-initiated intensive public health measures weeks. Respiratory hygiene had the highest compliance above 41% whereas hand hygiene was the lowest (4%). There was a significant difference between residents of the capital city and regional cities in their level of compliance with NPI. Females comply more than males, and individuals had increased NPI compliance at the bank service and workplaces compared to those in the transport services at P = 0.000. Conclusion An increased level of compliance with NPI was observed following intensive government-initiated Covid-19 prevention measures and an increased Covid-19 death incidence. Therefore, the intensity of government-initiated risk communication and public advocacy programs should be strengthened, possibly for similar respiratory disease pandemics in the future.
Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities

Background: Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. Purpose of the Study: This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology. Materials and Methods: The in vitro studies were conducted using fluorescence-based high throughput assays using human c-DNA baculovirus expressed CYP enzymes. For measuring CYP2E1 activity, a validated High-performance liquid chromatography (HPLC) assay was utilized to measure the formation of 6-hydroxychlorzoxazone. Results: The obtained half-maximum inhibitory concentration values with known positive control inhibitors of this study were comparable to the published values indicating accurate experimental techniques. Although QR did not show any significant effect on CYP1A2 and CYP2E1, it exhibited a strong inhibitory effect against CYP2D6 and a moderate effect against CYP2C19 and CYP3A4. On the other hand, TQ demonstrated a strong and a moderate inhibitory effect against CYP3A4 and CYP2C19, respectively. Conclusions: The findings of this study may indicate that consumption of QR or TQ, in the form of food or dietary supplements, with drugs that are metabolized by CYP2C19, CYP2D6, or CYP3A4 may cause significant herb-drug interactions. Abbreviations used: ABT: Aminobenztriazole, BZF: 7,8 Benzoflavone, CYP: Cytochrome P450, GB: Gingko Biloba, IC50: Half-maximum inhibitory concentration, KTZ: Ketoconazole, QND: Quinidine, QR: Quercetin, TCP: Tranylcypromine, TQ: Thymoquinone.
The Relationship Between Tumor Budding and Patient’s Survival in Breast Cancer

Introduction: Breast cancer is a severe life-threatening condition in which many women are involved yearly. One factor that has recently been noticed and investigated as a diagnostic predictor of this type of cancer is the number of tumor buds and the relation of this factor with a patient’s survival rate. Materials and methods: This study includes 150 female patients over 18 years old with a mean age of 53.99 ± 12.56 years old with breast cancer, which was diagnosed at various medical centers, including Rouhani Hospital itself, and referred to Rouhani Hospital Medical Center, Babol, Iran. The number of intratumoral and peritumoral buds in patients’ microscopic slides were archived and evaluated along with tumor microenvironment on hematoxylin and eosin (H&E) slides and compared to other clinicopathological findings. This article precisely investigated the relationship between the number of intratumoral and peritumoral buds with patients’ 5-year survival rate. Also, the relationship between age, tumor stage, grade, size, the number of lymph nodes involved, and the presence of metastasis with the number of intratumoral and peritumoral buds was studied. Results and discussion: The result showed a significant statistical association between the number of intratumoral and peritumoral buds with tumor size, tumor stage, presence of metastasis, the number of lymph nodes involved, and 5-year survival rate. On the other hand, there is not a significant statistical association between the number of intratumoral and peritumoral buds with age and tumor grade. Conclusion: Our investigation revealed a significant statistical relationship between the number of tumor buds and patients’ survival rate. So, this factor should be considered significant to help those patients increase their survival ratio.
Inside-Out Regulation of ICAM-1 Dynamics in TNF-α-Activated Endothelium

Background During transendothelial migration, leukocytes use adhesion molecules, such as ICAM-1, to adhere to the endothelium. ICAM-1 is a dynamic molecule that is localized in the apical membrane of the endothelium and clusters upon binding to leukocytes. However, not much is known about the regulation of ICAM-1 clustering and whether membrane dynamics are linked to the ability of ICAM-1 to cluster and bind leukocyte integrins. Therefore, we studied the dynamics of endothelial ICAM-1 under non-clustered and clustered conditions. Principal Findings Detailed scanning electron and fluorescent microscopy showed that the apical surface of endothelial cells constitutively forms small filopodia-like protrusions that are positive for ICAM-1 and freely move within the lateral plane of the membrane. Clustering of ICAM-1, using anti-ICAM-1 antibody-coated beads, efficiently and rapidly recruits ICAM-1. Using fluorescence recovery after photo-bleaching (FRAP), we found that clustering increased the immobile fraction of ICAM-1, compared to non-clustered ICAM-1. This shift required the intracellular portion of ICAM-1. Moreover, biochemical assays showed that ICAM-1 clustering recruited beta-actin and filamin. Cytochalasin B, which interferes with actin polymerization, delayed the clustering of ICAM-1. In addition, we could show that cytochalasin B decreased the immobile fraction of clustered ICAM-1-GFP, but had no effect on non-clustered ICAM-1. Also, the motor protein myosin-II is recruited to ICAM-1 adhesion sites and its inhibition increased the immobile fraction of both non-clustered and clustered ICAM-1. Finally, blocking Rac1 activation, the formation of lipid rafts, myosin-II activity or actin polymerization, but not Src, reduced the adhesive function of ICAM-1, tested under physiological flow conditions. Conclusions Together, these findings indicate that ICAM-1 clustering is regulated in an inside-out fashion through the actin cytoskeleton. Overall, these data indicate that signaling events within the endothelium are required for efficient ICAM-1-mediated leukocyte adhesion.
Alzheimer's disease heterogeneity revealed by neuroanatomical normative modeling

Abstract INTRODUCTION Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD‐related atrophy. METHODS We applied neuroanatomical normative modeling to magnetic resonance imaging from a real‐world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual‐ and group‐levels. RESULTS The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non‐amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo‐clinical correlations in individual patients.
A Study of Factors Affecting Functional Outcomes in Patients With Successful Recanalization by Mechanical Thrombectomy

Background and purpose: Reperfusion therapy is typically performed in cases with acute cerebral infarction. Mechanical thrombectomy (MT) achieves superior recanalization and favorable outcomes. However, some patients have poor functional prognosis despite successful recanalization. We investigated factors affecting functional prognosis after MT with good reperfusion. Methods: Among the 205 consecutive cases with ischemic stroke treated with MT at our center from January 1, 2019 to March 31, 2021, 168 with successful recanalization were included. Factors affecting early neurological improvement (ENI) and modified Rankin Scale (mRS) scores were reviewed retrospectively. Results: There were 93 (55%) cases with ENI and 75 (45%) without ENI. The times from onset to recombinant tissue-type plasminogen activator administration and recanalization in ENI cases were shorter than those in non-ENI cases. However, non-ENI cases had significantly higher Fazekas grades for white matter lesions. In multivariate analysis, the Fazekas grade was related to ENI (odds ratio [OR]=0.572, 95% confidence interval [CI]=0.345-0.948). The mRS score at discharge was 0-2 in 64 cases (good outcome) and 3-6 in 104 cases (poor outcome). Patients with a poor outcome had a significantly higher age, National Institutes of Health Stroke Scale (NIHSS) score, and Fazekas grade. Multivariate analysis revealed that the NIHSS score (OR=1.073, 95% CI=1.020-1.129) and Fazekas grade (OR=2.162, 95% CI=1.458-3.205) at hospitalization affected the mRS score at discharge. Conclusion: There is a correlation of greater severity of white matter lesions with poorer ENI and clinical outcomes at discharge post-MT.
Trends in Management of Ménière Disease: A TriNetX Network Database Analysis

Abstract This study investigated management practices for Meniere's disease (MD) and their temporal trends from 2008 to 2022 within the TriNetX network database. Study cohort included adult patients (≥18 years) with the diagnosis of MD from TriNetX's multi‐institutional medical records (n = 77,493). MD diagnosis and management were queried based on the international classification of diseases, tenth revision, current procedural terminology, and RXNorm codes. Temporal trends were analyzed using joinpoint regression. There was significant increase in rates of relevant medications prescribed within 12 months of MD diagnosis from 2008 to 2022 (annual percent change [APC]: 1.2 [95% confidence interval, CI: 0.4–1.9]). There were no significant changes in rate of intratympanic injection within 12 months of MD diagnosis (1.7 [95% CI: −1.1 to 4.5]). Rate of endolymphatic sac surgery and labyrinthectomy any time after MD diagnosis gradually decreased from 2008 to 2022 at APC of −8.1 (95% CI: −11.8 to −4.2) and −11.0 (95% CI: −14.0 to −7.7), respectively. Use of relevant medications has significantly increased during the early management of MD and the overall use of surgical treatments has decreased.
Lipid emulsion treatment for local anesthetic systemic toxicity in pediatric patients: A systematic review

Background: Local anesthetic systemic toxicity (LAST) is rare, but fatal; the current widely used treatment is lipid emulsion (LE). The goal of this study was to analyze and review case reports on LE treatment for LAST in pediatric patients. Methods: We performed a systematic review using case reports on LE treatment for LAST in pediatric patients, searching PubMed and Scopus databases to March 2023 using the following keywords: (“local anesthetic toxicity” OR “local anesthetic systemic toxicity” OR LAST”) AND (“newborn” OR “infant” OR “child” OR “children” OR “adolescent” OR “pediatric”) AND (“lipid emulsion” OR “Intralipid”). Results: Our search yielded 21 cases, revealing that nearly 43% patients with LAST were less than 1 year old, and most cases were caused by bupivacaine (approximately 67% cases). “Inadvertent intravascular injection” by anesthesiologists and “overdose of local anesthetics” mainly by surgeons were responsible for 52% and 24% cases of LAST, respectively. LAST occurred in the awake state (52%) and under general anesthesia (48%), mainly causing seizures and arrhythmia, respectively. Approximately 55% of patients received LE treatment in <10 minutes after LAST, mainly improving cardiovascular symptoms. A 20% LE (1.5 mL/kg) dose followed by 0.25 mL/kg/minutes dose was frequently used. LE and anticonvulsants were mainly used in the awake state, whereas LE with or without vasopressors was mainly used under general anesthesia. LE treatment led to full recovery from LAST in 20 cases; however, 1 patient died due to underlying disease. Conclusion: Consequently, our findings reveal that LE is effective in treating pediatric LAST.