Miracle-dz/UniFAR-FTUs huggingface dataset:
Study on the therapeutic effect of levetiracetam as an additive therapy for refractory partial epilepsy and the relativity between levetiracetam and multidrug resistance gene:a randomised double-blind placebo-controlled trial

Objective To investigate the therapeutic effect of levetiracetam as an additive therapy for refractory partial epilepsy and the relativity between levetiracetam and multidrug resistance gene 1 (MDR1). Methods Thirty patients with confirmed refractory partial epilepsy enrolled in a randomised, doubled-blind, placebo-controlled trial. The patients were given antiepileptic drug levetiracetam and placebo, respectively. The initiall dose was 1 g (2 / d), 2 weeks later the dose was increased to 2 g (2 / d), and another 2 weeks later increased to 3 g (2 / d). When achieving the above mentioned dose, the dosage was maintained for 12 weeks, then gradually decremented and turn to dose decrement / open period. Assessed the rate of seizure frequency in every week during the 16-week treatment period. Compared with the baseline period, evaluated the percentage of seizure frequency decrement and the effective rate of 50% seizure frequency decrement. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect genetype. Results Among 30 patients, 27 accomplished the trial. In genetype test, there were 16 patients with CC genetype including 9 in levetiracetam group (one case with completely controlled, 3 obviously effective and 2 effective; the effective rate of 50% seizure frequency decrement was 66.67%) and 7 in control group (only one effective; the effective rate of 50% seizure frequency decrement was 14.29%), and 11 patients with CT + TT genetype including 9 in levetiracetam group (one case with completely controlled, 2 obviously effective and 4 effective; the effective rate of 50% seizure frequency decrement was 77.78%) and 2 in controlgroup. The difference of therapeutic efficiency between the patients with CC genetype in levetiracetam group and thosein control group was significant (Z = -2.013, P = 0.042). There was no significant therapeutic efficiency difference between the patients with CC genetype and those with CT + TT genetype (Z = -0.193, P = 0.888). Conclusion Levetiracetam as an additive therapy has better therapeutic effect in the treatment for refractory partial epilepsy. The pharmacological mechanism of levetiracetam treatment for refractory epilepsy may be mainly related to levetiracetam which was not the P-glycoprotein (P-gp) substrate encoded by MDR1.
Effects of the molecular weight and molar ratio of poly(2-ethyl-2-oxazoline)-based lipid on the pH sensitivity, stability, and antitumor efficacy of liposomes

Abstract In this study, we evaluated and screened the effects of the molecular weight (MW) and molar ratio of poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEtOz-CHMC) on the pH sensitivity, stability, and antitumor efficacy of liposomes. The pH sensitivity of PEtOz-CHMC with different MWs and molar ratios was screened by drug release and cytotoxicity experiments at different pH levels. Results indicated that the liposomes coated with PEtOz1k-CHMC (7% molar ratio) and PEtOz2k-CHMC (5% molar ratio) exhibited the desirable pH responsiveness. When the MW of PEtOz was relatively low, 7% of the modified ratio obtained the strongest stability, but the turbidity of the liposomes did not obviously change when the molar ratio of PEtOz-CHMC was further increased. A375 cells were used as models to investigate the cellular uptake and intracellular localization of coumarin-6-loaded liposomes (C6-L), PEGylated liposomes (PEG-C6-L), and PEtOzylated liposomes. PEtOz1k-C6-L and PEtOz2k-C6-L presented remarkably stronger fluorescence intensity at low pH than at pH 7.4, whereas C6-L and PEG-C6-L did not achieve any obvious diversity at different pH conditions. Compared with C6-L and PEG-C6-L, PEtOz-C6-L showed efficient intracellular trafficking, including endosomal/lysosomal escape and cytoplasmic release. Pharmacokinetic experiments demonstrated that half-lives of PEG2k-C6-L, PEtOz2k-C6-L, and PEtOz1k-C6-L were 11.89-, 7.00-, and 5.29-fold times higher than those of C6-L, respectively. Among the liposomes, the DOX·HCl-loaded liposomes coated with PEtOz2k-CHMC demonstrated the strongest antitumor efficacy against B16 tumor xenograft models in vivo. These findings provide the feasibility of using PEtOz-CHMC with optimal pH sensitivity and long circulation to extend the application of liposomes to efficient anticancer drug delivery.
ATP binding cassette transporters ABCG1 and ABCG16 affect reproductive development via auxin signaling in Arabidopsis.

Angiosperm reproductive development is a complex event that includes floral organ development, male and female gametophyte formation and interaction between the male and female reproductive organs for successful fertilization. Previous studies revealed the redundant function of ATP binding cassette subfamily G (ABCG) transporters ABCG1 and ABCG16 in pollen development, but whether they are involved in other reproductive processes is unknown. Here we showed that ABCG1 and ABCG16 were not only expressed in anthers and stamen filaments but also enriched in pistil tissues, including the stigma, style, transmitting tract and ovule. We further demonstrated that pistil-expressed ABCG1 and ABCG16 promoted rapid pollen tube growth through their effects on auxin distribution and auxin flow in the pistil. Moreover, disrupted auxin homeostasis in stamen filaments was associated with defective filament elongation. Our work reveals the key functions of ABCG1 and ABCG16 in reproductive development and provides clues for identifying ABCG1 and ABCG16 substrates in Arabidopsis.
Genome Improvement and Core Gene Set Refinement of Fugacium kawagutii

Cataloging an accurate functional gene set for the Symbiodiniaceae species is crucial for addressing biological questions of dinoflagellate symbiosis with corals and other invertebrates. To improve the gene models of Fugacium kawagutii, we conducted high-throughput chromosome conformation capture (Hi-C) for the genome and Illumina combined with PacBio sequencing for the transcriptome to achieve a new genome assembly and gene prediction. A 0.937-Gbp assembly of F. kawagutii were obtained, with a N50 > 13 Mbp and the longest scaffold of 121 Mbp capped with telomere motif at both ends. Gene annotation produced 45,192 protein-coding genes, among which, 11,984 are new compared to previous versions of the genome. The newly identified genes are mainly enriched in 38 KEGG pathways including N-Glycan biosynthesis, mRNA surveillance pathway, cell cycle, autophagy, mitophagy, and fatty acid synthesis, which are important for symbiosis, nutrition, and reproduction. The newly identified genes also included those encoding O-methyltransferase (O-MT), 3-dehydroquinate synthase, homologous-pairing protein 2-like (HOP2) and meiosis protein 2 (MEI2), which function in mycosporine-like amino acids (MAAs) biosynthesis and sexual reproduction, respectively. The improved version of the gene set (Fugka_Geneset _V3) raised transcriptomic read mapping rate from 33% to 54% and BUSCO match from 29% to 55%. Further differential gene expression analysis yielded a set of stably expressed genes under variable trace metal conditions, of which 115 with annotated functions have recently been found to be stably expressed under three other conditions, thus further developing the “core gene set” of F. kawagutii. This improved genome will prove useful for future Symbiodiniaceae transcriptomic, gene structure, and gene expression studies, and the refined “core gene set” will be a valuable resource from which to develop reference genes for gene expression studies.
NR2A-NMDA Receptor Blockade Reverses the Lack of Morphine Analgesia Without Affecting Chronic Pain Status in a Fibromyalgia-Like Mouse Model

We have developed an experimental fibromyalgia-like mouse model using intermittent cold stress (ICS), where chronic pain is generalized, female predominant, and abolished in type 1 lysophosphatidic acid receptor-knockout (LPA1 -/-) mice but is not reversed by systemic or brain treatment with morphine. We investigated two issues in the present study: (1) whether chronic pain mechanisms and lack of brain morphine analgesia are associated in the ICS model and (2) what mechanisms are involved in the lack of morphine analgesia. ICS-induced hyperalgesia was not affected in μ-opioid receptor-knockout (MOPr -/-) mice, whereas the lack of brain morphine analgesia remained unchanged in LPA1 -/- mice, which completely abolished the hyperalgesia in the ICS model. In contrast, the lack of morphine analgesia was abolished in NR2A-NMDA receptor-knockout (NR2A -/-) mice and blocked by intracerebroventricular (i.c.v.) injection of (R)-CPP, an NR2A antagonist, or by microinjection of siRNA NR2A into the periaqueductal gray matter region, whereas no change was observed with Ro 04-5595, an NMDA receptor subtype 2B antagonist (i.c.v.). The lack of morphine analgesia was also reversed by concomitant treatment with 1 mg/kg intraperitoneal (i.p.) of dextromethorphan, which possesses NMDA receptor antagonist activity but no analgesic activity. Finally, the hyperalgesia was completely reversed by methadone, which possesses both MOPr agonist and NMDA receptor antagonist activity. Indeed, methadone analgesia was abolished in MOPr -/- mice. These results suggest that chronic pain status and lack of morphine analgesia are independent of each other, and that lack of morphine analgesia is mediated by activation of the NR2A-NMDA receptor system. SIGNIFICANCE STATEMENT This study reports that a type of intermittently repeated stress causes widespread pain that does not respond to morphine. Because this lack of morphine analgesia is not affected in mice, in which chronic pain is abolished, the mechanisms underlying chronic pain and lack of morphine analgesia are independent of each other. Through speculation that a lack of morphine analgesia may be a secondary event to endogenous opioid analgesic tolerance, the authors demonstrate that an antiopioid N-methyl-D-aspartate receptor system counterbalances the μ-opioid receptor–mediated analgesic mechanisms in the intermittent cold stress model.
Single- versus double-injection costoclavicular block: a randomized comparison

Background The costoclavicular approach targets the brachial plexus in the proximal infraclavicular fossa, where the lateral, medial, and posterior cords are tightly bundled together. This randomized trial compared single- and double-injection ultrasound-guided costoclavicular blocks. We selected onset time as the primary outcome and hypothesized that, compared with its single-injection counterpart, the double-injection technique would result in a swifter onset. Methods Ninety patients undergoing upper limb surgery (at or below the elbow joint) were randomly allocated to receive a single- (n=45) or double-injection (n=45) ultrasound-guided costoclavicular block. The local anesthetic agent (35 mL of lidocaine 1%-bupivacaine 0.25%with epinephrine 5 µg/mL and 2 mg of preservative-free dexamethasone) was identical in all subjects. In the single-injection group, the entire volume of local anesthetic was injected between the three cords of the brachial plexus. In the double-injection group, the first half of the volume was administered in this location; the second half was deposited between the medial cord and the subclavian artery. After the performance of the block, a blinded observer recorded the onset time (defined as the time required to achieve a minimal sensorimotor composite score of 14 out of 16 points), success rate (surgical anesthesia) and block-related pain scores. Performance time and the number of needle passes were also recorded during the performance of the block. The total anesthesia-related time was defined as the sum of the performance and onset times. Results Compared with its single-injection counterpart, the double-injection technique displayed shorter onset time (16.6 (6.4) vs 23.4 (6.9) min; p<0.001; 95% CI for difference 3.9 to 9.7) and total anesthesia-related time (22.5 (6.7) vs 28.9 (7.6) min; p<0.001). No intergroup differences were found in terms of success and technical execution (ie, performance time/procedural pain). The double-injection group required more needle passes than the single-injection group (2 (1–4) vs 1 (1–3); p<0.001). Conclusion Compared with its single-injection counterpart, double-injection costoclavicular block results in shorter onset and total anesthesia-related times. Further investigation is required to determine if a triple-injection technique (with targeted local anesthetic injection around each cord of the brachial plexus) could further decrease the onset time. Trial registration number NCT03595514.
Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element

Nucleocytoplasmic transport of unspliced and partially spliced human immunodeficiency virus (HIV) RNA is mediated in part by the Rev response element (RRE), a ~350 nt cis-acting element located in the envelope coding region of the viral genome. Understanding the interaction of the RRE with the viral Rev protein, cellular co-factors, and its therapeutic potential has been the subject of almost three decades of structural studies, throughout which a recurring discussion theme has been RRE topology, i.e., whether it comprises 4 or 5 stem-loops (SLs) and whether this has biological significance. Moreover, while in vitro mutagenesis allows the construction of 4 SL and 5 SL RRE conformers and testing of their roles in cell culture, it has not been immediately clear if such findings can be translated to a clinical setting. Herein, we review several articles demonstrating remarkable flexibility of the HIV-1 and HIV-2 RREs following initial observations that HIV-1 resistance to trans-dominant Rev therapy was founded in structural rearrangement of its RRE. These observations can be extended not only to cell culture studies demonstrating a growth advantage for the 5 SL RRE conformer but also to evolution in RRE topology in patient isolates. Finally, RRE conformational flexibility provides a target for therapeutic intervention, and we describe high throughput screening approaches to exploit this property.
Sex as a biological variable in irritable bowel syndrome

The pathophysiology and mechanisms of irritable bowel syndrome (IBS) involve both central and peripheral mechanisms that result in altered perception, as well as changes in bowel functions. These dysfunctions are associated with motor, sensory, immune, barrier, and intraluminal perturbations, including the microbiota, and their products and endogenous molecules with bioactive properties. There is evidence that these mechanisms are altered in both females and males. However, there is also increasing evidence that sex is a biological variable that impacts a number of aspects of the mechanisms, epidemiology, and manifestations of IBS.
CD5 blockade enhances ex vivo CD8+ T cell activation and tumour cell cytotoxicity

CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate TCR signalling and impair CTL activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti‐tumour activity against tumours (including solid tumours) has not been explored. CD5 knockout mice show increased anti‐tumour immunity: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti‐tumour response. Here, we show that ex vivo administration of a function‐blocking anti‐CD5 MAb to primary mouse CTLs of both tumour‐naïve mice and mice bearing murine 4T1 breast tumour homografts enhanced their capacity to respond to activation by treatment with anti‐CD3/anti‐CD28 MAbs or 4T1 tumour cell lysates. Furthermore, it enhanced TCR signalling (ERK activation) and increased markers of T cell activation, including proliferation, CD69 levels, IFN‐γ production, apoptosis and Fas receptor and Fas ligand levels. Finally, CD5 function‐blocking MAb treatment enhanced the capacity of CD8+ T cells to kill 4T1‐mouse tumour cells in an ex vivo assay. These data support the potential of blockade of CD5 function to enhance T cell‐mediated anti‐tumour immunity.
Cumulative Integration of Academically Advanced Honors College Students

The study sought to understand what caused, or is causing, Murray State University Honors College students to become successful in post-secondary education. The researcher chose to extend the findings of previous research beyond the freshmen year and focus exclusively on what influences persistence until graduation for second, third, or fourth-year students. While research that influences graduation is not a new idea, emphasis on influential factors that affect upperlevel college students remains relatively unexplored. The whole student consisting of domains that consider social integration, academic integration, intrinsic motivation, and key interactions that intermingle throughout the collegiate journey was taken into consideration to discover what has prepared these students for cumulative integration to occur. The study provided a qualitative view of how Honors College students at MSU perceive that they have cumulatively integrated into their environment using observations, a focus group, and individual interviews as primary data collection methodologies. The results were transcribed and coded to reveal three dominant domains: community, preparatory experiences, and self-discovery. Findings help to advance research in the area of student success by viewing the whole student and the cumulative integration beyond the freshmen level.
The Apoplastic and Symplastic Antioxidant System in Onion: Response to Long-Term Salt Stress

The response of apoplastic antioxidant systems in root and leaf tissues from two onion genotypes (‘Texas 502’, salt-sensitive and ‘Granex 429’, salt-resistant) in response to salinity was studied. Electrolyte leakage data indicated the membrane integrity impairing by the effect of salts, especially in ‘Texas 502’. We detected superoxide dismutase (SOD) and peroxidase (POX) activity in the root and leaf apoplastic fractions from onion plants. Salinity increased SOD activity in the root symplast of ‘Texas 502’ and in ‘Granex 429’ leaves. In contrast, salinity reduced SOD activity in the leaf and root apoplastic fractions from ‘Texas 502’. In ‘Granex 429’, salt-stress increased leaf apoplastic POX activity and symplastic catalase (CAT) activity of both organs, but a decline in root apoplastic POX from ‘Texas 502’ took place. Salt-stress increased monodehydroascorbate reductase (MDHAR) in root and leaf symplast and in root glutathione reductase GR, mainly in ‘Granex 429’, but only in this genotype, leaf dehydroascorbate reductase (DHAR) activity increased. In contrast, a decline in leaf GR was produced only in ‘Texas 502’. Salinity increased leaf ASC levels, and no accumulation of dehydroascorbate (DHA) was observed in roots in both cases. These responses increased the redox state of ascorbate, especially in roots. In contrast, salinity declined reduced glutathione (GSH), but oxidised glutathione (GSSG) was accumulated in leaves, decreasing the redox state of glutathione. Salinity slightly increased root GSH concentration in the salt-tolerant genotype and was unchanged in the salt-sensitive genotype, but no accumulation of GSSG was produced, favoring the rise and/or maintenance of the redox state of the glutathione. These results suggest that the lower sensitivity to salt in ‘Granex 429’ could be related to a better performance of the antioxidant machinery under salinity conditions.
Thromboembolic and bleeding risk of periprocedural bridging anticoagulation: A systematic review and meta‐analysis

The risk and benefit of periprocedural heparin bridging is not completely clarified. We aimed to assess the safety and efficacy of bridging anticoagulation prior to invasive procedures or surgery. Heparin bridging was associated with lower risks of thromboembolism and bleeding compared to non‐bridging. PubMed, Ovid and Elsevier, and Cochrane Library (2000‐2016) were searched for English‐language studies. Studies comparing interrupted anticoagulation with or without bridging and continuous oral anticoagulation in patients at moderate‐to‐high thromboembolic risk before invasive procedures were included. Primary outcomes were thromboembolic events and bleeding events. Mantel‐Haenszel method and random‐effects models were used to analyze the pooled risk ratio (RR) and 95% confidence interval (CI) for thromboembolic and bleeding risks. Eighteen studies (six randomized controlled trials and 12 cohort studies) were included (N = 23 364). There was no difference in thromboembolic risk between bridged and non‐bridged patients (RR: 1.26, 95% CI: 0.61‐2.58; RCTs: RR: 0.71, 95% CI: 0.23‐2.24; cohorts: RR: 1.45, 95% CI: 0.63‐3.37). However, bridging anticoagulation was associated with higher risk of overall bleeding (RR: 2.83, 95% CI: 2.00‐4.01; RCTs: RR: 2.24, 95% CI: 0.99‐5.09; cohorts: RR: 3.09, 95% CI: 2.07‐4.62) and major bleeding (RR: 3.00, 95% CI: 1.78‐5.06; RCTs: RR: 2.48, 95% CI: 1.29‐4.76; cohorts: RR: 3.22, 95% CI: 1.65‐6.32). Bridging anticoagulation was associated with increased bleeding risk compared to non‐bridging. Thromboembolism risk was similar between two strategies. Our results do not support routine use of bridging during anticoagulation interruption.
A Novel Cost-Efficient Framework for Critical Heartbeat Task Scheduling Using the Internet of Medical Things in a Fog Cloud System

Recently, there has been a cloud-based Internet of Medical Things (IoMT) solution offering different healthcare services to wearable sensor devices for patients. These services are global, and can be invoked anywhere at any place. Especially, electrocardiogram (ECG) sensors, such as Lead I and Lead II, demands continuous cloud services for real-time execution. However, these services are paid and need a lower cost-efficient process for the users. In this paper, this study considered critical heartbeat cost-efficient task scheduling problems for healthcare applications in the fog cloud system. The objective was to offer omnipresent cloud services to the generated data with minimum cost. This study proposed a novel health care based fog cloud system (HCBFS) to collect, analyze, and determine the process of critical tasks of the heartbeat medical application for the purpose of minimizing the total cost. This study devised a health care awareness cost-efficient task scheduling (HCCETS) algorithm framework, which not only schedule all tasks with minimum cost, but also executes them on their deadlines. Performance evaluation shows that the proposed task scheduling algorithm framework outperformed the existing algorithm methods in terms of cost.
Mis‐annotations of a promising antibiotic target in high‐priority gram‐negative pathogens

The rise of antibiotic resistance combined with the lack of new products entering the market has led to bacterial infections becoming one of the biggest threats to global health. Therefore, there is an urgent need to identify novel antibiotic targets, such as dihydrodipicolinate synthase (DHDPS), an enzyme involved in the production of essential metabolites in cell wall and protein synthesis. Here, we utilised a 7‐residue sequence motif to identify mis‐annotation of multiple DHDPS genes in the high‐priority Gram‐negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. We subsequently confirmed these mis‐annotations using a combination of enzyme kinetics and X‐ray crystallography. Thus, this study highlights the need to ensure genes encoding promising drug targets, like DHDPS, are annotated correctly, especially for clinically important pathogens.