Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolution and transmission of a conjugative plasmid encoding both ciprofloxacin and ceftriaxone resistance in Salmonella

ABSTRACT Ceftriaxone and ciprofloxacin are the drugs of choice in treatment of invasive Salmonella infections. This study discovered a novel type of plasmid, pSa44-CIP-CRO, which was recovered from a S. London strain isolated from meat product and comprised genetic determinants that encoded resistance to both ciprofloxacin and ceftriaxone. This plasmid could be resolved into two daughter plasmids and co-exist with such daughter plasmids in a dynamic form in Salmonella; yet it was only present as a single plasmid in Escherichia coli. One daughter plasmid, pSa44-CRO, was found to carry the blaCTX-M-130 gene, which encodes resistance to ceftriaxone, whereas the other plasmid, pSa44-CIP, carried multiple PMQR genes such as qnrB6-aac(6’)-Ib-cr, which mediated resistance to ciprofloxacin. These two daughter plasmids could be integrated into one single plasmid through ISPa40 mediated homologous recombination. Mouse infection and treatment experiments showed that carriage of plasmid, pSa44-CIP-CRO by S. typhimurium led to the impairment of treatment by ciprofloxacin or cefitiofur, a veterinary drug with similar properties as ceftriaxone. In conclusion, dissemination of such conjugative plasmids impairs current choices of treatment for life-threatening Salmonella infection and hence constitutes a serious public health threat.
From single drug targets to synergistic network pharmacology in ischemic stroke

Significance Current one drug–one target–one disease approaches in drug discovery have become increasingly inefficient. Network pharmacology defines disease mechanisms as networks best targeted by multiple, synergistic drugs. Using the high unmet medical need indication stroke, we here develop an integrative in silico approach based on a primary target, NADPH oxidase type 4, to identify a mechanistically related cotarget, NO synthase, for network pharmacology. Indeed, we validate both in vivo and in vitro, including humans, that both NOX4 and NOS inhibition is highly synergistic, leading to a significant reduction of infarct volume, direct neuroprotection, and blood–brain-barrier stabilization. This systems medicine approach provides a ground plan to decrease current failure in the field by being implemented in other complex indications. Drug discovery faces an efficacy crisis to which ineffective mainly single-target and symptom-based rather than mechanistic approaches have contributed. We here explore a mechanism-based disease definition for network pharmacology. Beginning with a primary causal target, we extend this to a second using guilt-by-association analysis. We then validate our prediction and explore synergy using both cellular in vitro and mouse in vivo models. As a disease model we chose ischemic stroke, one of the highest unmet medical need indications in medicine, and reactive oxygen species forming NADPH oxidase type 4 (Nox4) as a primary causal therapeutic target. For network analysis, we use classical protein–protein interactions but also metabolite-dependent interactions. Based on this protein–metabolite network, we conduct a gene ontology-based semantic similarity ranking to find suitable synergistic cotargets for network pharmacology. We identify the nitric oxide synthase (Nos1 to 3) gene family as the closest target to Nox4. Indeed, when combining a NOS and a NOX inhibitor at subthreshold concentrations, we observe pharmacological synergy as evidenced by reduced cell death, reduced infarct size, stabilized blood–brain barrier, reduced reoxygenation-induced leakage, and preserved neuromotor function, all in a supraadditive manner. Thus, protein–metabolite network analysis, for example guilt by association, can predict and pair synergistic mechanistic disease targets for systems medicine-driven network pharmacology. Such approaches may in the future reduce the risk of failure in single-target and symptom-based drug discovery and therapy.
Topicalizer: reframing core concepts in machine learning visualization by co-designing for interpretivist scholarship

Topicalizer: reframing core concepts in machine learning visualization by co-designing for interpretivist scholarship Eric P. S. Baumer, Drew Siedel, Lena McDonnell, Jiayun Zhong, Patricia Sittikul & Micki McGee To cite this article: Eric P. S. Baumer, Drew Siedel, Lena McDonnell, Jiayun Zhong, Patricia Sittikul & Micki McGee (2020): Topicalizer: reframing core concepts in machine learning visualization by co-designing for interpretivist scholarship, Human–Computer Interaction, DOI: 10.1080/07370024.2020. 1734460 To link to this article: https://doi.org/10.1080/07370024.2020. 1734460
P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation.

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals. " P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R-/-) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R-/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R-/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R-/- mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R-/- mice. Irradiated P2X7R-/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.
Childhood Health Motivation and Adult Cardiometabolic Health in the Childhood Determinants of Adult Health (CDAH) Study

Objective: This research examined if childhood health motivation was associated with adult health behaviors and objectively measured health outcomes. Method: Data were from the Childhood Determinants of Adult Health study. Children aged 9 to 15 years in 1985 completed a questionnaire with health motivation items. In 2004–2006, when aged 26 to 36, participants completed assessments of health behaviors (smoking, diet, alcohol consumption, and physical activity) and cardiometabolic outcomes (body mass index, carotid intima-media thickness from ultrasound, and HOMA insulin resistance from fasting blood samples). Structural path regression analyses examined pathways from health motivation in childhood to adult cardiometabolic outcomes, mediated via adult health behaviors measured concurrently, controlling for age, sex and socioeconomic position. Results: There were 6,230 (49% female) children with data on health motivation. There were two latent constructs: health motivation (4 items: visiting a dentist, visiting a doctor, knowing about your body, and eating a good diet) and risk motivation (3 items: not being a smoker, not being fat, and not drinking alcohol). Greater health motivation was directly associated with nonsmoking, lower carotid intima-media thickness, and lower body mass index in adulthood. Greater risk motivation was directly associated with smoking, higher alcohol consumption, and poorer diets in adulthood. It was also indirectly associated with higher carotid intima-media thickness and higher HOMA insulin resistance via poorer health behaviors. Conclusions: Health motivation during childhood appears important to maintain health across the life course. It could be a target for interventions to improve cardiovascular health in children and adults.
Fibrosis evolution in chronic hepatitis B e antigen‐negative patients across a 10‐year interval

The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long‐term dynamic changes of liver fibrosis are limited. This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10‐year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow‐up LSM. Fibrosis stages were classified according to EASL‐ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)‐negative patients (224 untreated, 235 treated with nucleos(t)ide analogues [NAs]) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval [CI]: 1.032‐4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128‐16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271‐26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = −0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis‐related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB‐related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time‐dependent decline in liver stiffness.
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.

BACKGROUND Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. RESULTS CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. CONCLUSION CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. TRIAL REGISTRATION NCT02546167. FUNDING University of Pennsylvania-Novartis Alliance and NIH.
Versatile Multi-Functional Block Copolymers Made by Atom Transfer Radical Polymerization and Post-Synthetic Modification: Switching from Volatile Organic Compound Sensors to Polymeric Surfactants for Water Rheology Control via Hydrolysis

Novel, multipurpose terpolymers based on styrene (PS), tert-butyl methacrylate (tBMA) and glycidyl methacrylate (GMA), have been synthesized via Atom Transfer Radical Polymerization (ATRP). Post-synthetic modification with 1-pyrenemethylamine (AMP) allows non-covalent functionalization of carbon nanotubes, eventually yielding a conductive nanocomposite materials capable of interacting with different Volatile Organic Compounds (VOCs) by electrical resistance variation upon exposure. Moreover, facile hydrolysis of the tBMA group yields polyelectrolytic macrosurfactants with remarkable thickening properties for promising applications in water solution, such as Enhanced Oil Recovery (EOR).
Improving transient performance of discrete‐time model reference adaptive control architectures

Discrete‐time adaptive control algorithms can be executed directly in embedded code unlike their continuous‐time counterparts, which require discretization. However, their designs predicated on quadratic Lyapunov‐based frameworks are quite intricate due to the resulting complexity in the Lyapunov difference expressions. Therefore, a wide array of available continuous‐time results addressing transient performance issues using adaptive control algorithms cannot be applied or readily extended to the discrete‐time case. In this article, we present a new model reference adaptive control architecture for discrete‐time uncertain dynamical systems. Specifically, the proposed architecture consists of a command governor mechanism that adjusts the trajectory of a given command during the closed‐loop transient response. It is shown that this mechanism is effective in improving transient performance of discrete‐time model reference adaptive control architectures. Using a logarithmic Lyapunov function, we prove Lyapunov stability of the closed‐loop system as well as asymptotic convergence of the system error states involving the difference between the states of the uncertain dynamical system and the states of the reference model, as well as driving the command governor signal to zero.
Effect of conservative treatment in aortoiliac occlusive disease

Abstract Objective: To determine the effect of primary conservative treatment without revascularization in patients with proven aortoiliac occlusive disease (AIOD) presenting with intermittent claudication (IC). Background: The initial treatment of IC should focus on supervised exercise therapy (SET) and pharmacotherapy. Nowadays, primary endovascular revascularization (EVR) has become increasingly popular in patients with all types of AIOD. But in daily practice, EVR is often performed without initially extensive exercise. Method: This is a single centre retrospective study from December 2012 to September 2017. Primary outcomes were maximum walking distance (MWD) and patient satisfaction. Secondary outcomes were revascularization rate and mortality. Results: Twenty-four patients were included. Mean age was 64 years (SD: 9). Mean follow-up was 28 months (SD: 17). Nineteen patients (80%) had SET. In 18 (75%) patients, the MWD was improved compared to the initial situation. In five (21%) patients, the MWD stayed the same. The MWD of one (4%) patient decreased. Overall satisfaction rate was 87%. Three patients (13%) were not satisfied with the conservative treatment and eventually got an EVR. There was no disease related death. Conclusions: Conservative treatment, especially with SET, has acceptable subjective symptom outcomes in selected patients with AIOD. It could be a good alternative treatment for certain patients with AIOD and IC.
Making Competitive Cities in the Light of the Meta-SWOT Tool: A Case Study of Tehran, Iran

ABSTRACT While there is a growing body of scholarship on regional competitiveness, little attention has been paid to the planning methods that can pursue this objective. Public planners are mainly relying on conventional methods that have come under increasing criticism. This study aims to introduce Meta-SWOT as a novel planning tool in urban and regional studies. Meta-SWOT provides competitive and realistic strategies for planners. It systematically tries to present strategies rooted in internal resources and capabilities while acknowledging the challenges posed by the external environment. Nevertheless, it has several limitations that should be considered when applying to urban and regional planning.
CRISPR Interference for Rapid Knockdown of Essential Cell Cycle Genes in Lactobacillus plantarum

L. plantarum is an important bacterium for applications in food and health. Deep insights into the biology and physiology of this species are therefore necessary for further strain optimization and exploitation; however, the functions of essential genes in the bacterium are mainly unknown due to the lack of accessible genetic tools. The CRISPRi system developed here is ideal to quickly screen for phenotypes of both essential and nonessential genes. Our initial insights into the function of some key cell cycle genes represent the first step toward understanding the cell cycle in this bacterium. ABSTRACT Studies of essential genes in bacteria are often hampered by the lack of accessible genetic tools. This is also the case for Lactobacillus plantarum, a key species in food and health applications. Here, we develop a clustered regularly interspaced short palindromic repeat interference (CRISPRi) system for knockdown of gene expression in L. plantarum. The two-plasmid CRISPRi system, in which a nuclease-inactivated Cas9 (dCas9) and a gene-specific single guide RNA (sgRNA) are expressed on separate plasmids, allows efficient knockdown of expression of any gene of interest. We utilized the CRISPRi system to gain initial insights into the functions of key cell cycle genes in L. plantarum. As a proof of concept, we investigated the phenotypes resulting from knockdowns of the cell wall hydrolase-encoding acm2 gene and of the DNA replication initiator gene dnaA and of ezrA, which encodes an early cell division protein. Furthermore, we studied the phenotypes of three cell division genes which have recently been functionally characterized in ovococcal bacteria but whose functions have not yet been investigated in rod-shaped bacteria. We show that the transmembrane CozE proteins do not seem to play any major role in cell division in L. plantarum. On the other hand, RNA-binding proteins KhpA and EloR are critical for proper cell elongation in this bacterium. IMPORTANCE L. plantarum is an important bacterium for applications in food and health. Deep insights into the biology and physiology of this species are therefore necessary for further strain optimization and exploitation; however, the functions of essential genes in the bacterium are mainly unknown due to the lack of accessible genetic tools. The CRISPRi system developed here is ideal to quickly screen for phenotypes of both essential and nonessential genes. Our initial insights into the function of some key cell cycle genes represent the first step toward understanding the cell cycle in this bacterium.
A REVIEW OF MOTIVATION THEORIES, MODELS AND INSTRUMENTS IN LEARNING ENVIRONMENT

Motivation is vital for students to face obstacles to achieving their aspirations. Consistent or natural motivation levels are not adequate to achieve academic and career rates. It takes a strong motivation to persevere in the pursuit of academic or life achievement. The goal of this paper is to perform a literature review to identify motivational theories, models, and motivational questionnaires that can support a technology-based learning environment. The results from the literature review discovered that there are several theories for measuring motivation, intrinsic theory, and extrinsic motivation theory, self-determination theory, ARCS model, social cognitive theory, and expectancy theory. Also, there are several questionnaires that are suitable for the learning environment such as Instructional Material Motivation Study (IMMS), Motivation Score for Questionnaire Learning (MSLQ), Student Motivation for Science Questionnaire (SMTSL), and Self-Regulation of Motivation Academic (SRAM). The results of this paper are intended for teachers, educators and scholars interested in enhancing the learning motivation of their students.
Analyzing the effects of pixel-scale data fusion in hyperspectral image classification performance

Recently, multispectral and hyperspectral data fusion models based on deep learning have been proposed to generate images with a high spatial and spectral resolution. The general objective is to obtain images that improve spatial resolution while preserving high spectral content. In this work, two deep learning data fusion techniques are characterized in terms of classification accuracy. These methods fuse a high spatial resolution multispectral image with a lower spatial resolution hyperspectral image to generate a high spatial-spectral hyperspectral image. The first model is based on a multi-scale long short-term memory (LSTM) network. The LSTM approach performs the fusion using a multiple step process that transitions from low to high spatial resolution using an intermediate step capable of reducing spatial information loss while preserving spectral content. The second fusion model is based on a convolutional neural network (CNN) data fusion approach. We present fused images using four multi-source datasets with different spatial and spectral resolutions. Both models provide fused images with increased spatial resolution from 8m to 1m. The obtained fused images using the two models are evaluated in terms of classification accuracy on several classifiers: Minimum Distance, Support Vector Machines, Class-Dependent Sparse Representation and CNN classification. The classification results show better performance in both overall and average accuracy for the images generated with the multi-scale LSTM fusion over the CNN fusion.
Role of imaging techniques in liver veno-occlusive disease diagnosis: recent advances and literature review

ABSTRACT Introduction: Veno-occlusive-disease (VOD), known also as sinusoidal-obstruction-syndrome (SOS), is one of the main complications of haematopoietic stem cell transplantation and is related to the treatment with pyrrolizidine alkaloids or other toxic agents (chemotherapy for liver-metastasis). Clinical diagnosis using the recent criteria from the European Society for Blood and Marrow Transplantation, is the reference for VOD/SOS diagnosis. However, increasing evidence suggests the emerging role of several imaging methods that could help the clinician in VOD/SOS assessment. Areas covered: This review evaluates the current literature on the various imaging techniques used in VOD/SOS diagnosis in several clinical scenarios. Literature searches were performed using several keywords on MEDLINE/Ovid/In-Process/Cochrane Library/EMBASE and PubMed up to July 2018. Expert commentary: Hepatic-gradient-measurement (HVPG) and contextual transjugular-liver-biopsy are invasive and should always be considered in unclear cases. The main studies revolve around ultrasound with Doppler evaluation, identifying numerous findings suggestive of VOD/SOS. However, their accuracy and validation are still suboptimal and controversial. CT-Scan and MRI have shown encouraging data in other contexts in which VOD/SOS can develop, but studies on the post-HSCT patient are lacking. Elastography techniques measuring liver stiffness (LSM) represent the most recent and promising approach for an accurate and early diagnosis of VOD/SOS. In our view, a multidisciplinary approach to the VOD/SOS diagnosis should be highly encouraged.