Miracle-dz/UniFAR-FTUs huggingface dataset:
Development and Application of a Data-Driven Reaction Classification Model: Comparison of an Electronic Lab Notebook and Medicinal Chemistry Literature

Reaction classification has often been considered an important task for many different applications, and has traditionally been accomplished using hand-coded rule-based approaches. However, the availability of large collections of reactions enables data-driven approaches to be developed. We present the development and validation of a 336-class machine learning-based classification model integrated within a Conformal Prediction (CP) framework in order to associate reaction class predictions with confidence estimations. We also propose a data-driven approach for 'dynamic' reaction fingerprinting to maximise the effectiveness of reaction encoding, as well as developing a novel reaction classification system that organises labels in four hierarchical levels (SHREC: Sheffield Hierarchical REaction Classification). We show that the performance of the CP augmented model can be improved by defining confidence thresholds to detect predictions that are less likely to be false. For example, the external validation of the model reports 95% of predictions as correct by filtering out less than 15% of the uncertain classifications. The application of the model is demonstrated by classifying two reaction datasets: one extracted from an industrial ELN and the other from the medicinal chemistry literature. We show how confidence estimations and class compositions across different levels of information can be used to gain immediate insights on the nature of reaction collections and hidden relationship between reaction classes.
MicroRNA Mediated Changes in Drug Metabolism and Target Gene Expression by Efavirenz and Rifampicin In Vitro: Clinical Implications

Abstract Efavirenz (EFV) and rifampicin (RMP) are widely prescribed in Africa for treatment of HIV/AIDS and tuberculosis epidemics. Exposure to medicines can alter drug metabolism, for example, through changes in expression of microRNAs. We report, in this study, novel observations on the ways in which EFV and RMP change microRNA expression signatures in vitro in HepaRG cells. Additionally, we discuss the clinical implications of changes in expression of drug-metabolizing enzyme genes, such as CYP3A4, CYP3A5, UGT1A1, CYP2B6, and NR1I3. Differentiated HepaRG cells were treated with EFV (6.4 μM) or RMP (24.4 μM) for 24 h. Treatment of HepaRG cells with EFV resulted in a significant increase in messenger RNA (mRNA) expression for CYP3A4 (12.51-fold, p = 0.002), CYP3A5 (2.10-fold, p = 0.019), and UGT1A1 (2.52-fold, p = 0.005), whereas NR1I3 expression decreased (0.41-fold, p = 0.02). On the other hand, treatment of HepaRG cells with RMP resulted in a significant increase in mRNA expression for CYP2B6 (6.68-fold, p = 0.007) and CYP3A4 (111.96-fold, p = 0.001), whereas NR1I3 expression decreased (0.46-fold, p = 0.033). These data point to several important clinical implications through changes in drug/drug interaction risks and achieving optimal therapeutics. All in all, this study shows that differential expression of microRNAs after treatment with EFV and RMP adds another layer of complexity that should be incorporated in pharmacogenomic algorithms to render drug response more predictable.
The Influence of Psychological Predictors and Cognitive Behavioral Stress Management Intervention on Antiretroviral Therapy (ART) Adherence Among HIV-Positive Female Haitian Alcohol Users

Antiretroviral Therapy (ART) Adherence Among HIV-Positive Female Haitian Alcohol Users, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. iii DEDICATION This dissertation is dedicated to my parents Lionel and Maud Jean for all the sacrifices that they made so that my siblings and I could have all the opportunities in order to live a fulfilled life. This is also dedicated to my grandparents for teaching me about the role of family and about faith. Most importantly, this is dedicated to Haiti and the people of Haiti, for teaching me about perseverance and how to overcome adversities. I hope that with this PhD, I am able to make a difference for the people of Haiti and similar communities. iv ACKNOWLEDGMENTS First, I would like to thank my dissertation committee members, Dr. time and guidance throughout the years and dissertation process. A special thank you to Dr. Michèle Jean-Gilles and Charlene Brown for providing me with a great deal of support and advice during this process. Thank you to all my professors, both in Dietetics and Nutrition and in Public Health, as well as the staff and fellow students at FIU who I have had the pleasure of meeting. A million thanks to my family and support system. Manmie, Papi, Christine and Junior; no words could express my gratitude for the significant role that you play in my life; thank you for loving me and supporting me. Thank you to my wonderful niece and nephew, Leah and Karim for giving me pure joy; being your Tatie Pas is my greatest accomplishment. A special thank you to Stephanie Wade and Cetremia Roberts, for the calls, texts, encouraging quotes, emails and prayers which help me survived the dissertation writing process. Finally, I would like to thank Tania Rivera and Marie Sandra Severe for their friendship and unconditional support through the final stages of this dissertation process.
Serine 19 phosphorylation and 14‐3‐3 binding regulate phosphorylation and dephosphorylation of tyrosine hydroxylase on serine 31 and serine 40

Multisite phosphorylation and structural flexibility allow for complex regulation of proteins through cellular signaling. Tyrosine hydroxylase (TH), a key enzyme of catecholamine synthesis, is regulated by multiple neuronal signaling pathways through phosphorylation at serine 19 (Ser19), serine 31 (Ser31), and serine 40 (Ser40) located in the flexible, far N‐terminal region of the regulatory domain. Phosphorylated Ser19 (pSer19) provides a binding site for 14‐3‐3 proteins, a family of multi‐target binding adaptor proteins. We hypothesized that pSer19 and 14‐3‐3 binding can regulate access to the Ser31 and Ser40 sites and modulate the dynamics of their phosphorylation state. To avoid complications from upstream signal interactions and have good control of TH‐phosphorylation and 14‐3‐3 binding stoichiometry, we used purified recombinant human TH and 14‐3‐3 dimer types. We found that pSer19 strongly stimulated Ser31 phosphorylation (4.6‐fold), but inhibited pSer31 dephosphorylation (3.4‐fold). Binding of 14‐3‐3ζ counteracted the stimulatory effect of pSer19 on phosphorylation at Ser31, but amplified the effect on its dephosphorylation. In contrast, phosphorylation at Ser19 had moderate effect on pSer40 dephosphorylation, but 14‐3‐3ζ binding inhibited dephosphorylation, an effect that was consistent across different homo‐ and heterodimeric 14‐3‐3s. Additional phosphorylation of Ser31 or Ser40 had little impact on the binding affinity of pSer19 TH to 14‐3‐3s. Mathematical modeling was performed to elucidate possible physiological implications of these observations. We propose a role of Ser19 and 14‐3‐3 proteins as modulators of TH phosphorylation in response to neuronal co‐signaling events. These mechanisms add to our understanding of the multifaceted roles of phosphorylation and adaptor proteins in cellular signaling.
Teaching in the Middle School

I: UNDERSTANDING MIDDLE SCHOOLS AND YOUNG ADOLESCENTS. 1. Middle Schools Today-Concepts and Teaching. 2. Young Adolescents-Development and Issues. II: DEVELOPING THE CURRICULUM AND ORGANIZING THE SCHOOL. 3. Middle School Curriculum-Core and Related Domains. 4. Middle School Curriculum-Integrated and Exploratory. III. PLANNING, IMPLEMENTING, ASSESSING, AND MANAGING INSTRUCTION. 5. Planning Instruction-Appropriate and Interdisciplinary. 6. Implementing Instruction-Organization, Methods, and Materials. 7. Assessment of Learning-Methods and Issues. 8. Managing Young Adolescents and Environments-Strategies and Techniques. IV: GUIDING STUDENTS AND WORKING WITH EXTERNAL COMMUNITIES. 9. Guiding Young Adolescents-Teachers and Counselors. 10. Parents, Families, and Community Members-Partners and Resources. 11. Epilogue: Middle Schools of the Future. Glossary. References. Author Index. Subject Index.
A 5-Year Review of Hospital Costs and Reimbursement in the Surgical Management of Degenerative Spondylolisthesis

ABSTRACT Background To evaluate charges, expenses, reimbursement, and hospital margins with noninstrumented posterolateral fusion in situ (PLF), posterolateral fusion with pedicle screws (PPS), and PPS with interbody device (PLIF) in degenerative spondylolisthesis with spinal stenosis. Methods A retrospective chart review was performed from 2010 to 2014 based on ICD-9 diagnoses of degenerative spondylolisthesis with spinal stenosis in patients undergoing single-level fusions. All charges, expenses, reimbursement, and margins were obtained through financial auditing. A multivariate linear regression model was used to compare demographics, charges, etc. A 1-way analysis of variance with Tukey post hoc analysis was used to analyze reimbursements and margins based upon insurances. Results Two hundred thirty-three patients met inclusion criteria. The overall charges and expenses for PLF were significantly less compared to both types of instrumented fusions (P < .0001). Medicare and private insurance were the most common insurance types; Medicare and private insurance mean reimbursements for PLF were $36,903 and $47,086, respectively; for PPS, $37,450 and $53,851, and for PLIF $40,171 and $51,640. Hospital margins for PPS and PLIF in Medicaid patients were negative (−$3,702 and −$6,456). Hospital margins were largest for both worker's compensation and private insurance patients in all fusion groups. Hospital margins with Medicare for PLF, PPS, and PLIF were $24,347, $19,205, and $23,046, respectively. Hospital margins for private insurance for PLF, PPS, and PLIF were $37,569, $36,834, and $33,134, respectively. Conclusions As more instrumentation is used, the more it costs both the hospital and the insurance companies; hospital margins did not increase correspondingly. Clinical Relevance Improved understanding of related costs and margins associated with lumbar fusions to help transition to more cost effective spine centers.
Presenilin-1 Established ER-Ca2+ Leak: a Follow Up on Its Importance for the Initial Insulin Secretion in Pancreatic Islets and β-Cells upon Elevated Glucose.

BACKGROUND/AIMS In our recent work, the importance of GSK3β-mediated phosphorylation of presenilin-1 as crucial process to establish a Ca2+ leak in the endoplasmic reticulum and, subsequently, the pre-activation of resting mitochondrial activity in β-cells was demonstrated. The present work is a follow-up and reveals the importance of GSK3β-phosphorylated presenilin-1 for responsiveness of pancreatic islets and β-cells to elevated glucose in terms of cytosolic Ca2+ spiking and insulin secretion. METHODS Freshly isolated pancreatic islets and the two pancreatic β-cell lines INS-1 and MIN-6 were used. Cytosolic Ca2+ was fluorometrically monitored using Fura-2/AM and cellular insulin content and secretion were measured by ELISA. RESULTS Our data strengthened our previous findings of the existence of a presenilin-1-mediated ER-Ca2+ leak in β-cells, since a reduction of presenilin-1 expression strongly counteracted the ER Ca2+ leak. Furthermore, our data revealed that cytosolic Ca2+ spiking upon administration of high D-glucose was delayed in onset time and strongly reduced in amplitude and frequency upon siRNA-mediated knock-down of presenilin-1 or the inhibition of GSK3β in the pancreatic β-cells. Moreover, glucose-triggered initial insulin secretion disappeared by depletion from presenilin-1 and inhibition of GSK3β in the pancreatic β-cells and isolated pancreatic islets, respectively. CONCLUSION These data complement our previous work and demonstrate that the sensitivity of pancreatic islets and β-cells to glucose illustrated as glucose-triggered cytosolic Ca2+ spiking and initial but not long-lasting insulin secretion crucially depends on a strong ER Ca2+ leak that is due to the phosphorylation of presenilin-1 by GSK3β, a phenomenon that might be involved in the development of type 2 diabetes.
The Effect of Hyperbaric Oxygen Treatment on Myoblasts and Muscles After Contusion Injury

The recommended treatment varies depending on the severity of muscle injuries. The aim of this study was to evaluate the in vitro myoblast proliferation and the in vivo histologic and physiologic effects of hyperbaric oxygen treatment on muscle healing after contusion. Cells from the C2C12 myoblast cell line were exposed to 100% O2 for 25 min then to air for 5 min at 2.5 atmospheres absolute in a hyperbaric chamber for a total treatment duration of 90 min per 48 h at intervals of 2, 4, 6 and 8 days. Cell growth measurements and western blot analysis of myogenin and actin were performed. Then, 18 mice aged 8–10 weeks were used in the muscle contusion model. The histologic and physiologic effects and muscle regeneration after hyperbaric oxygen treatment were evaluated. The myoblast growth rate was significantly higher (p < 0.05) after hyperbaric oxygen treatment. Densitometric evaluation demonstrated a 39% (p < 0.05) and 25% (p < 0.05) increase in myogenin and actin protein levels, respectively, in the cells treated with 1 dose of hyperbaric oxygen. Similarly, the myogenin and actin protein levels increased for samples receiving multiple hyperbaric oxygen treatments when compared with the control. Physiologic evaluation of fast twitch and tetanus strength revealed a significant difference between the control group and the 14‐day hyperbaric oxygen group. In conclusion, hyperbaric oxygen treatment increases the myoblast growth rate and myogenin and actin production. Better histologic and physiologic performance were found after hyperbaric oxygen treatment in animal contusion model. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:329‐335, 2020
Stent-assisted coiling of cerebral aneurysms: multi-center analysis of radiographic and clinical outcomes in 659 patients

Introduction The endovascular stent-assisted coiling approach for the treatment of cerebral aneurysms is evolving rapidly with the availability of new stent devices. It remains unknown how each type of stent affects the safety and efficacy of the stent-coiling procedure. Methods This study compared the outcomes of endovascular coiling of cerebral aneurysms using Neuroform (NEU), Enterprise (EP), and Low-profile Visualized Intraluminal Support (LVIS) stents. Patient characteristics, treatment details and angiographic results using the Raymond–Roy grade scale (RRGS), and procedural complications were analyzed in our study. Results Our study included 659 patients with 670 cerebral aneurysms treated with stent-assisted coiling (NEU, n=182; EP, n=158; LVIS, n=330) that were retrospectively collected from six academic centers. Patient characteristics included mean age 56.3±12.1 years old, female prevalence 73.9%, and aneurysm rupture on initial presentation of 18.8%. We found differences in complete occlusion on baseline imaging, defined as RRGS I, among the three stents: LVIS 64.4%, 210/326; NEU 56.2%, 95/169; EP 47.6%, 68/143; P=0.008. The difference of complete occlusion on 10.5 months (mean) and 8 months (median) angiographic follow-up remained significant: LVIS 84%, 251/299; NEU 78%, 117/150; EP 67%, 83/123; P=0.004. There were 7% (47/670) intra-procedural complications and 11.5% (73/632) post-procedural-related complications in our cohort. Furthermore, procedure-related complications were higher in the braided-stents vs laser-cut, P=0.002. Conclusions There was a great variability in techniques and choice of stent type for stent-assisted coiling among the participating centers. The type of stent was associated with immediate and long-term angiographic outcomes. Randomized prospective trials comparing the different types of stents are warranted.
The Role of Heme Oxygenase-1 in Remote Ischemic and Anesthetic Organ Conditioning

The cytoprotective effects of the heme oxygenase (HO) pathway are widely acknowledged. These effects are mainly mediated by degradation of free, pro-oxidant heme and the generation of carbon monoxide (CO) and biliverdin. The underlying mechanisms of protection include anti-oxidant, anti-apoptotic, anti-inflammatory and vasodilatory properties. Upregulation of the inducible isoform HO-1 under stress conditions plays a crucial role in preventing or reducing cell damage. Therefore, modulation of the HO-1 system might provide an efficient strategy for organ protection. Pharmacological agents investigated in the context of organ conditioning include clinically used anesthetics and sedatives. A review from Hoetzel and Schmidt from 2010 nicely summarized the effects of anesthetics on HO-1 expression and their role in disease models. They concluded that HO-1 upregulation by anesthetics might prevent or at least reduce organ injury due to harmful stimuli. Due to its clinical safety, anesthetic conditioning might represent an attractive pharmacological tool for HO-1 modulation in patients. Remote ischemic conditioning (RIC), first described in 1993, represents a similar secure option to induce organ protection, especially in its non-invasive form. The efficacy of RIC has been intensively studied herein, including on patients. Studies on the role of RIC in influencing HO-1 expression to induce organ protection are emerging. In the first part of this review, recently published pre-clinical and clinical studies investigating the effects of anesthetics on HO-1 expression patterns, the underlying signaling pathways mediating modulation and its causative role in organ protection are summarized. The second part of this review sums up the effects of RIC.
Stochastic Variation in Expression of the Tricarboxylic Acid Cycle Produces Persister Cells

Persister cells are rare phenotypic variants that are able to survive antibiotic treatment. Unlike resistant bacteria, which have specific mechanisms to prevent antibiotics from binding to their targets, persisters evade antibiotic killing by entering a tolerant nongrowing state. Persisters have been implicated in chronic infections in multiple species, and growing evidence suggests that persister cells are responsible for many cases of antibiotic treatment failure. New antibiotic treatment strategies aim to kill tolerant persister cells more effectively, but the mechanism of tolerance has remained unclear until now. ABSTRACT Chronic bacterial infections are difficult to eradicate, though they are caused primarily by drug-susceptible pathogens. Antibiotic-tolerant persisters largely account for this paradox. In spite of their significance in the recalcitrance of chronic infections, the mechanism of persister formation is poorly understood. We previously reported that a decrease in ATP levels leads to drug tolerance in Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. We reasoned that stochastic fluctuation in the expression of tricarboxylic acid (TCA) cycle enzymes can produce cells with low energy levels. S. aureus knockouts in glutamate dehydrogenase, 2-oxoketoglutarate dehydrogenase, succinyl coenzyme A (CoA) synthetase, and fumarase have low ATP levels and exhibit increased tolerance of fluoroquinolone, aminoglycoside, and β-lactam antibiotics. Fluorescence-activated cell sorter (FACS) analysis of TCA genes shows a broad Gaussian distribution in a population, with differences of over 3 orders of magnitude in the levels of expression between individual cells. Sorted cells with low levels of TCA enzyme expression have an increased tolerance of antibiotic treatment. These findings suggest that fluctuations in the levels of expression of energy-generating components serve as a mechanism of persister formation. IMPORTANCE Persister cells are rare phenotypic variants that are able to survive antibiotic treatment. Unlike resistant bacteria, which have specific mechanisms to prevent antibiotics from binding to their targets, persisters evade antibiotic killing by entering a tolerant nongrowing state. Persisters have been implicated in chronic infections in multiple species, and growing evidence suggests that persister cells are responsible for many cases of antibiotic treatment failure. New antibiotic treatment strategies aim to kill tolerant persister cells more effectively, but the mechanism of tolerance has remained unclear until now.
Do Microinjury Mechanisms Complement Inflammation in Sacroiliac Joint Ankylosis on Magnetic Resonance Imaging of Young Spondyloarthritis Patients? Comment on the Article by Bray et al

Bray and colleagues (1) deserve compliment on their report of magnetic resonance imaging (MRI) scores of inflammation and structural damage of sacroiliac joints (SIJs) in 29 young (ages 12-23 years) spondyloarthritis (SpA) patients. All patients had undergone at least 3 MRI scans of the SIJs over at least a 2-year period with at least 1 scan conducted before or at the time of starting tumor necrosis factor inhibitor (TNFi) therapy (1).
Grazing simplifies soil micro‐food webs and decouples their relationships with ecosystem functions in grasslands

Livestock grazing often alters aboveground and belowground communities of grasslands and their mediated carbon (C) and nitrogen (N) cycling processes at the local scale. Yet, few have examined whether grazing‐induced changes in soil food webs and their ecosystem functions can be extrapolated to a regional scale. We investigated how large herbivore grazing affects soil micro‐food webs (microbes and nematodes) and ecosystem functions (soil C and N mineralization), using paired grazed and ungrazed plots at 10 locations across the Mongolian Plateau. Our results showed that grazing not only affected plant variables (e.g., biomass and C and N concentrations), but also altered soil substrates (e.g., C and N contents) and soil environment (e.g., soil pH and bulk density). Grazing had strong bottom‐up effects on soil micro‐food webs, leading to more pronounced decreases at higher trophic levels (nematodes) than at lower trophic levels (microbes). Structural equation modeling showed that changes in plant biomass and soil environment dominated grazing effects on microbes, while nematodes were mainly influenced by changes in plant biomass and soil C and N contents; the grazing effects, however, differed greatly among functional groups in the soil micro‐food webs. Grazing reduced soil C and N mineralization rates via changes in plant biomass, soil C and N contents, and soil environment across grasslands on the Mongolian Plateau. Spearman's rank correlation analysis also showed that grazing reduced the correlations between functional groups in soil micro‐food webs and then weakened the correlation between soil micro‐food webs and soil C and N mineralization. These results suggest that changes in soil micro‐food webs resulting from livestock grazing are poor predictors of soil C and N processes at regional scale, and that the relationships between soil food webs and ecosystem functions depend on spatial scales and land‐use changes.