Miracle-dz/UniFAR-FTUs huggingface dataset:
Deciphering the tetrad of epigenetic cytosine modifications

A tetrad of epigenetic cytosine modifications imbues the DNA code with complex, dynamic meaning. DNA methyltransferase enzymes deposit methyl marks on the 5-carbon of cytosine, forming 5-methylcytosine (mC), which generally mediates long-term, locus-specific transcriptional repression during development and reprogramming. Ten-eleven translocation (TET) family enzymes oxidize the methyl group in three steps, forming predominantly 5-hydroxymethylcytosine (hmC) but also low levels of 5-formylcytosine (fC) and 5-carboxylcytosine (caC). These additional bases likely provide pathways for erasing methylation, but they may also harbor epigenetic functions in their own right. Questions regarding how each base forms and functions drive at the fundamental biology of the epigenome. In this thesis, I chronicle our lab’s efforts to probe the epigenome at its source—by deciphering and manipulating TET enzyme mechanisms. In particular, we aim to understand how and why TET enzymes generate rare fC and caC bases rather than hmC alone. Following a review of the field, I describe in Chapter 2 the methods that we developed to study rare cytosine modifications with high sensitivity. In Chapter 3, we applied these techniques to a rigorous kinetic study of how mouse Tet2 establishes and maintains oxidized cytosines. We found that Tet2 is capable of iterative oxidation, staying on a DNA strand to catalyze multiple rounds of oxidation and thereby enabling efficient generation of fC and caC under certain circumstances. In Chapter 4, we asked what structurefunction determinants could allow for the generation of fC and caC. We discovered a conserved active site scaffold in human TET2 that specifically supports the formation of all three oxidized bases, not just hmC. By mutating the active site, we could alter the interactions between key residues to achieve stalling of oxidation at hmC. These mutants have now paved the way for applications in model systems to examine the function of hmC independently of fC and caC, which will allow us to dissect whether the rare, highly oxidized bases are truly critical for epigenetic processes. I describe our progress to date in Chapter 5, along with further mechanistic explorations of the dynamic epigenome. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biochemistry & Molecular Biophysics First Advisor Rahul M. Kohli Second Advisor Benjamin A. Garcia This dissertation is available at ScholarlyCommons: https://repository.upenn. edu/edissertations/2430
Multiattribute Analysis of Trichomonas vaginalis Diagnostics and Its Correlation with Clinical Complaints and Contraceptive Methods in a Symptomatic Egyptian Cohort

Background Trichomonas vaginalis (T. vaginalis) infection has been long considered among the sexually transmitted diseases that possesses a clear effect on women's health especially in the childbearing period. Methods A 234 females of age range 18-45 years old attending the Gynecology and Obstetrics Outpatient Clinic of Kasr El Aini Hospitals were enrolled in a cross-sectional study. The taken vaginal swabs were subjected to wet mount microscopy, Giemsa stain, modified Diamond's culture, and nested polymerase chain reaction (nPCR) amplification. Multiattribute and analytical hierarchy processes were conducted to detect laboratory utility. Univariate and multivariate analyses were done to detect the multiple risk factors that may be associated with Trichomonas infection. Results Based on nPCR, the prevalence of trichomoniasis was 26.9%. Wet mount, Giemsa stain, and culture showed 100% specificity but of low sensitivity (28.57%, 28.57%, and 57.14%, respectively). On the multivariate analysis, nPCR showed the highest rank for diagnostic performance and culture had the lowest rank. For univariate analysis, there was a significant correlation between T. vaginalis infection and vaginal discharge, burning sensation, dyspareunia, and the use of intrauterine device (IUD) (P value < 0.05). Conclusion The routine screening of trichomoniasis using nPCR was reliable, sensitive, and specific. Also, it could financially be considered a more suitable option in batch screening. Significant higher rates of infection were reported among IUD users compared to condom or hormonal-based methods.
Log-based software monitoring: a systematic mapping study

Modern software development and operations rely on monitoring to understand how systems behave in production. The data provided by application logs and runtime environment are essential to detect and diagnose undesired behavior and improve system reliability. However, despite the rich ecosystem around industry-ready log solutions, monitoring complex systems and getting insights from log data remains a challenge. Researchers and practitioners have been actively working to address several challenges related to logs, e.g., how to effectively provide better tooling support for logging decisions to developers, how to effectively process and store log data, and how to extract insights from log data. A holistic view of the research effort on logging practices and automated log analysis is key to provide directions and disseminate the state-of-the-art for technology transfer. In this paper, we study 108 papers (72 research track papers, 24 journals, and 12 industry track papers) from different communities (e.g., machine learning, software engineering, and systems) and structure the research field in light of the life-cycle of log data. Our analysis shows that (1) logging is challenging not only in open-source projects but also in industry, (2) machine learning is a promising approach to enable a contextual analysis of source code for log recommendation but further investigation is required to assess the usability of those tools in practice, (3) few studies approached efficient persistence of log data, and (4) there are open opportunities to analyze application logs and to evaluate state-of-the-art log analysis techniques in a DevOps context.
Human Acquired Aplastic Anemia Patients' Bone-Marrow-Derived Mesenchymal Stem Cells Are Not Influenced by Hematopoietic Compartment and Maintain Stemness and Immune Properties

Methods In the current study, we investigated the morphological differences, proliferation capacity, population doubling time (PDT), surface marker profiling, trilineage differentiation potential, and immunosuppressive ability of BM Mesenchymal Stem Cells (BM-MSCs) from untreated aAA patients and in the same number of age- and gender-matched controls. Results We observed similar morphology, proliferation capacity, phenotype, trilineage differentiation potential, and immunomodulatory properties of BM-MSCs in aAA patients and control subjects. Conclusion Our results confirm that the basic and immunosuppressive properties of BM-MSCs from aAA patients do not differ from normal BM-MSCs. Our data suggest that BM-MSCs from aAA patients might not be involved in disease pathogenesis. However, owing to a smaller number of samples, it is not conclusive, and future studies with more exhaustive investigation at transcriptome level are warranted.
Comparing postoperative pain in various pressure pneumoperitoneum of laparoscopic cholecystectomy: a double-blind randomized controlled study

Purpose This study aims to evaluate the effect of different pneumoperitoneum pressures on postoperative pain, especially by subcategorizing the pressures into 3 groups during laparoscopic cholecystectomy (LC). Methods We conducted a prospective randomized, double-blinded study of 150 patients with benign and uncomplicated gallbladder disease. They were categorized into 3 groups. Each group (50 patients) underwent LC with different pneumoperitoneum methods: group VLP, very-low pressure (6–8 mmHg); group LP, low pressure (9–11 mmHg); and group SP, standard pressure (12–14 mmHg). The 3 groups were compared for pain intensity, duration, analgesic requirement, and complications. Results The characteristics of the patients were similar among all groups. Postoperative pain scores at each time point (1, 2, 4, 6, 12, 24, and 48 hours) were not significantly different among the 3 groups. Further, operation time, hospital stay, the number of analgesic consumption doses, and postoperative complications were not significantly different among the 3 groups. Conclusion This study demonstrates no difference in postoperative pain among various pneumoperitoneum pressures during LC. Therefore, routine use of lower-pressure pneumoperitoneum is not recommended unless in selected patients who require low-pressure pneumoperitoneum surgery.
Preparation, Pharmacokinetics, and Antitumor Potential of Miltefosine-Loaded Nanostructured Lipid Carriers

Background The purpose of this study was to investigate the suitability of nanostructured lipid carriers (NLCs) loaded with miltefosine (HePC) as an anticancer drug for the treatment of breast cancer. Methods HePC-NLCs were prepared using a microemulsion technique and then evaluated for particle size, polydispersity index (PDI), incorporation efficiency, in vitro release of entrapped drug, and hemolytic potential. Furthermore, pharmacokinetic, biodistribution, and liver toxicity analyses were performed in Sprague–Dawley rats, and antitumor efficacy was evaluated in Michigan Cancer Foundation-7 (MCF-7) and squamous cell carcinoma-7 (SCC-7) cells in vitro and in tumour-bearing BALB/c mice in vivo. Advanced analyses including survival rate, immunohistopathology, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assays were performed to evaluate apoptosis in vivo. Results The average particle size of the HePC-NLCs was 143 ± 16 nm, with a narrow PDI (0.104 ± 0.002), and the incorporation efficiency was found to be 91 ± 7%. The NLCs released HePC in a sustained manner, and this release was significantly lower than that of free drug. The in vitro hemolytic assay demonstrated a significantly reduced hemolytic potential (~9%) of the NLCs compared to that of the test formulations. The HePC-NLCs demonstrated enhanced pharmacokinetic behaviour over free drug, including extended blood circulation and an abridged clearance rate in rats. Furthermore, the HePC-NLCs exhibited higher cytotoxicity than the free drug in MCF-7 and SCC-7 cells. Moreover, the HePC-NLCs showed significantly enhanced (P < 0.005) antitumor activity compared to that of the control and free drug-treated mouse groups. Tumour cell apoptosis was also confirmed, indicating the antitumor potential of the HePC-NLCs. Conclusion These findings demonstrate the ability of NLCs as a drug delivery system for enhanced pharmacokinetic, antitumor, and apoptotic effects, most importantly when loaded with HePC.
Radiation Increases Bioavailability of Lisinopril, a Mitigator of Radiation-Induced Toxicities

There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA. Methods: Female WAG/RijCmcr rats were irradiated with 12.5–13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments. Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001). Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats.
Highly efficient and stable planar perovskite solar cells by solution-processed tin oxide

Perovskite solar cells (PSCs) are one of the most promising lab-scale technologies to deliver inexpensive solar electricity. Low-temperature planar PSCs are particularly suited for large-scale manufacturing. Here, we propose a simple, solution-processed technological approach for depositing SnO2 layers. The use of these layers in planar PSCs yields a high stabilized power conversion efficiency close to 21%, exhibiting stable performance under real operating conditions for over 60 hours. In addition, this method yielded remarkable voltages of 1214 mV at a band gap of 1.62 eV (approaching the thermodynamic limit of 1.32 V) confirming the high selectivity of the solution-processed layers. PSCs aged under 1 sun illumination and maximum power point tracking showed a final PCE of 20.7% after ageing and dark storage, which is slightly higher than the original efficiency. This approach represents an advancement in the understanding of the role of electron selective layers on the efficiency and stability of PSCs. Therefore, the newly proposed approach constitutes a simple, scalable method paving the way for industrialization of perovskite solar cells.
Expression Profile of Long Noncoding RNAs and Circular RNAs in Mouse C3H10T1/2 Mesenchymal Stem Cells Undergoing Myogenic and Cardiomyogenic Differentiation

Background Currently, a heterogeneous category of noncoding RNAs (ncRNA) that directly regulate the expression or function of protein-coding genes is shown to have an effect on the fate decision of stem cells. However, the detailed regulatory roles of ncRNAs in myogenic and cardiomyogenic differentiation of mouse C3H10T1/2 mesenchymal stem cells (MSCs) are far from clear. Methods In this study, 5-azacytidine- (5-AZA-) treated C3H10T1/2 cells were differentiated into myocyte-like and cardiomyocyte-like cells. Next, ncRNA associated with myogenic and cardiomyogenic differentiation was identified using high-throughput RNA sequencing (RNA-seq) data. Bioinformatics analysis was conducted to identify the differentially expressed ncRNAs and the related signaling pathways. Results Myotube-like structure was formed after 5-AZA treatment of C3H10T1/2 cells. In addition, myogenic and cardiomyogenic differentiation-related genes like GATA4, cTnt, MyoD, and Desmin were upregulated significantly after the 5-AZA treatment. Totally, 1538 differentially expressed lncRNAs and 3398 differentially expressed mRNAs were identified, including 1175 upregulated and 363 downregulated lncRNAs and 2429 upregulated and 969 downregulated mRNAs. In addition, 46 differentially expressed circRNAs were identified, including 25 upregulated and 21 downregulated circRNAs. Moreover, the differentially expressed mRNAs were enriched into 5 significant pathways, including those for focal adhesion, ECM-receptor interaction, PI3K-AKT signaling pathway, PPAR signaling pathway, and Tyrosine metabolism. Conclusions A systematic view of the expression of ncRNAs in myogenic and cardiomyogenic differentiation of MSCs was provided in the study.
Yes-Associated Protein is Involved in Myocardial Fibrosis in Rats with Diabetic Cardiomyopathy

Introduction Recent studies have shown that YAP is closely related to the pathological process of cardiovascular diseases. But the role of YAP in cardiac injury of diabetic cardiomyopathy (DCM) is still unclear. Methods Diabetic cardiomyopathy rat model was established and divided into control group, DCM group, LV-SC-shRNA group and LV-YAP-shRNA group. LV-SC-shRNA group and LV-YAP-shRNA group were injected with lentivirus expressing SC-shRNA and YAP-shRNA via tail vein, respectively. Primary rat cardiac fibroblasts (CFs) were stimulated with high concentration of glucose and treated with recombinant lentivirus expressing either SC-shRNA or YAP-shRNA to observe the expression of CTGF and fibronectin, so as to observe the effect of inhibiting YAP on the pathogenesis of DCM. Results Compared with control group, high glucose markedly increased YAP mRNA and protein expression in DCM and CFs. Inhibition of YAP decreased myocardial fibrosis and improved cardiac function in the DCM model and decreased the expression of CTGF and fibronectin in CFs. The result suggested that YAP plays a key role in the pathological progression of DCM, and the underlying mechanisms may be associated with TEAD and CTGF. Discussion We found that the expression of YAP was increased both in vivo and in vitro, suggesting that YAP is closely related to DCM, and YAP knockdown can reduce myocardial fibrosis in rat model of DCM by reducing the expression of PAI-1, collagen I, collagen III, CTGF and profilin, as well as the expression of CTGF and fibronectin in CFs. This study revealed that YAP plays an important role in the pathological process of diabetic cardiomyopathy, and down-regulation of YAP expression may provide a new therapeutic target for DCM.
Preparation and Evaluation of Lipid Emulsion Containing 13 Vitamins for Injection Without Anaphylactoid Reactions

Objective Multivitamins containing Tween 80 can cause anaphylactoid reactions. The objective of this study was to develop a new lipid emulsion containing 13 fat- and water-soluble vitamins for injection (13V-LE) that were simultaneously dissolved in one bottle and to evaluate the stability of and anaphylactoid reactions to 13V-LE. Methods Particle size, ζ-potential, and polydispersity of 13V-LE were assayed with a Zetasizer Nano ZS. Entrapment efficiency of 13V-LE was determined with HPLC. Behavior, histamine, and blood pressure of beagle dogs were investigated by observation, fluorospectrophotometry, and sphygmomanometry. Results The 13V-LE with the smallest particles and highest entrapment efficiency with stable ζ-potential was composed of soybean oil, glycerin (2.25%, w:v), egg lecithin (1.2%, w:v), and purified water. There was no obvious change in characteristics of the 13V-LE samples in terms of appearance, size distribution, ζ-potential, pH value, or concentration over 6 months. In anaphylactoid reactions tests, when being administered with the multivitamin Infuvite Adult containing Tween 80, six beagles showed grade IV symptoms (P<0.01 vs control), low blood pressure, and high plasma-histamine concentrations (P<0.05 or P<0.01). However, there were no significant differences in behavior, blood pressure, or histamine concentration in the dogs before and after administration in the 13V-LE group. Conclusion The 13V-LE formulation is a suitable intravenous lipid emulsion without anaphylactoid reactions.
Nitrogen: Root growth and nitrate uptake of vegetable crops

Root growth and nitrate uptake of spinach and kohlrabi were investigated in the field and in solution culture as affected by nitrate supply. Optimum Nmin supply of spinach and kohlrabi was 250 and 150 kg Nmin/ha, resp. Lower fertilization rates decreased shoot yield of both crops, whereas root yield was nearly doubled for spinanch but slightly diminished for kohlrabi. Thus, spinach had about twice as much root surface/g shoot at low than with optimum nitrate supply. Maximum rate of nitrate uptake (Imax) expressed per cm2 cylindrical root surface determined in solution culture was similar to the average uptake rate (UR) in the field for kohlrabi if optimum nitrate quantity was supplied. For spinach, however, UR was 5 times higher than Imax. Including root hair surface in addition to cylindrical root surface resulted in a close agreement between Imax and UR for spinach. Both crops absorbed nitrate at about maximum rate in the field. The nitrate concentration in soil solution which was necessary to .
Remote, unsupervised functional motor task evaluation in older adults across the United States using the MindCrowd electronic cohort

The COVID-19 pandemic has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. This study tested whether motor function can be assessed at home. One hundred seventy-seven older adults nationwide (recruited through the MindCrowd electronic cohort) completed a brief functional upper-extremity assessment at home and unsupervised. Performance data were compared to data from an independent sample of community-dwelling older adults (N=250) assessed by an experimenter in-lab. The effect of age on performance was similar between the in-lab and at-home groups for both the dominant and non-dominant hand. Practice effects were also similar between the groups. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution in response to the COVID-19 pandemic and telehealth practice and other research involving remote or geographically isolated individuals.
How advanced is the epidemiological transition in Papua New Guinea? New evidence from verbal autopsy

Abstract Background Reliable cause of death (COD) data are not available for the majority of deaths in Papua New Guinea (PNG), despite their critical policy value. Automated verbal autopsy (VA) methods, involving an interview and automated analysis to diagnose causes of community deaths, have recently been trialled in PNG. Here, we report VA results from three sites and highlight the utility of these methods to generate information about the leading CODs in the country. Methods VA methods were introduced in one district in each of three provinces: Alotau in Milne Bay; Tambul-Nebilyer in Western Highlands; and Talasea in West New Britain. VA interviews were conducted using the Population Health Metrics Research Consortium (PHMRC) shortened questionnaire and analysed using the SmartVA automated diagnostic algorithm. Results A total of 1655 VAs were collected between June 2018 and November 2019, 87.0% of which related to deaths at age 12 years and over. Our findings suggest a continuing high proportion of deaths due to infectious diseases (27.0%) and a lower proportion of deaths due to non-communicable diseases (NCDs) (50.8%) than estimated by the Global Burden of Disease Study (GBD) 2017: 16.5% infectious diseases and 70.5% NCDs. The proportion of injury deaths was also high compared with GBD: 22.5% versus 13.0%. Conclusions Health policy in PNG needs to address a ‘triple burden’ of high infectious mortality, rising NCDs and a high fraction of deaths due to injuries. This study demonstrates the potential of automated VA methods to generate timely, reliable and policy-relevant data on COD patterns in hard-to-reach populations in PNG.