Miracle-dz/UniFAR-FTUs huggingface dataset:
Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies

AIMS Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukaemia (CML). However, cardiotoxicity of these agents remains a serious concern. The underlying mechanism of these adverse cardiac effects is largely unknown. Delineation of the underlying mechanisms of TKIs associated cardiac dysfunction could guide potential prevention strategies, rescue approaches, and future drug design. This study aimed to determine the cardiotoxic potential of approved CML TKIs, define the associated signalling mechanism and identify potential alternatives. METHODS AND RESULTS In this study, we employed a zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter (nppb:F-Luciferase) to assess the cardiotoxicity of all approved CML TKIs. Our in vivo screen identified ponatinib as the most cardiotoxic agent among the approved CML TKIs. Then using a combination of zebrafish and isolated neonatal rat cardiomyocytes, we delineated the signalling mechanism of ponatinib-induced cardiotoxicity by demonstrating that ponatinib inhibits cardiac prosurvival signalling pathways AKT and extra-cellular-signal-regulated kinase (ERK), and induces cardiomyocyte apoptosis. As a proof of concept, we augmented AKT and ERK signalling by administration of Neuregulin-1β (NRG-1β), and this prevented ponatinib-induced cardiomyocyte apoptosis. We also demonstrate that ponatinib-induced cardiotoxicity is not mediated by inhibition of fibroblast growth factor signalling, a well-known target of ponatinib. Finally, our comparative profiling for the cardiotoxic potential of CML approved TKIs, identified asciminib (ABL001) as a potentially much less cardiotoxic treatment option for CML patients with the T315I mutation. CONCLUSION Herein, we used a combination of in vivo and in vitro methods to systematically screen CML TKIs for cardiotoxicity, identify novel molecular mechanisms for TKI cardiotoxicity, and identify less cardiotoxic alternatives.
Does a Novice Technician Produce Results Similar to That of an Experienced DXA Technician When Assessing Body Composition and Bone Mineral Density?

Dual-energy X-ray absorptiometry is a commonly used clinical assessment tool for body composition and bone mineral density, which is gaining popularity in athletic cohorts. Results from body composition scans are useful for athletic populations to track training and nutritional interventions, while bone mineral density scans are valuable for athletes at risk of developing stress fractures due to low bone mineral density. However, no research has ascertained if a novice technician (accredited but not experienced) could produce similar results to an experienced technician. Two groups of recreational athletes were scanned, one by an experienced technician, one by a novice technician. All participants were scanned twice with repositioning between scans. The experienced technician's reliability (intraclass correlation coefficient = .989-.998; percentage change in mean = -0.01 to 0.10), precision (typical error as coefficient of variation percentage = 0.01-0.47; SEM% = 0.61-1.39), and sensitivity to change (smallest real difference percentage = 1.70-3.85) were similar; however, superior to those of the novice technician. The novice technician results were reliability (intraclass correlation coefficient = .985-.997; percentage change in mean = -0.03 to 0.23), precision (typical error as coefficient of variation percentage = 0.03-0.75; SEM% = 1.06-2.12), and sensitivity to change (smallest real difference percentage = 2.73-5.86). Extensive experience, while valuable, is not a necessary requirement to produce quality results when undertaking whole-body dual-energy X-ray absorptiometry scanning.
Enabling Virtual AAA Management in SDN-Based IoT Networks †

The increase of Software Defined Networks (SDN) and Network Function Virtualization (NFV) technologies is bringing many security management benefits that can be exploited at the edge of Internet of Things (IoT) networks to deal with cyber-threats. In this sense, this paper presents and evaluates a novel policy-based and cyber-situational awareness security framework for continuous and dynamic management of Authentication, Authorization, Accounting (AAA) as well as Channel Protection virtual security functions in IoT networks enabled with SDN/NFV. The virtual AAA, including network authenticators, are deployed as VNF (Virtual Network Function) dynamically at the edge, in order to enable scalable device’s bootstrapping and managing the access control of IoT devices to the network. In addition, our solution allows distributing dynamically the necessary crypto-keys for IoT Machine to Machine (M2M) communications and deploy virtual Channel-protection proxys as VNFs, with the aim of establishing secure tunnels among IoT devices and services, according to the contextual decisions inferred by the cognitive framework. The solution has been implemented and evaluated, demonstrating its feasibility to manage dynamically AAA and channel protection in SDN/NFV-enabled IoT scenarios.
Community Asthma Initiative: Cost Analyses using Claims Data from a Medicaid Managed Care Organization

Abstract Objective: Use claims data to examine the cost benefit of the Community Asthma Initiative (CAI), a Boston area nurse-supervised community health worker (CHW) asthma home-visiting program. Methods: The reduction in asthma treatment costs was assessed using Massachusetts claims data from one Medicaid Managed Care Organization (MCO) in the north east that included all costs between January 1, 2011 and December 31, 2016. The data was used to determine asthma-related utilization cost reductions between 1 year pre- and 1, 2 and 3 years post-intervention. The cost reductions for 45 CAI patients and 45 cost-matched comparison patients were measured. Return on investment (ROI) was computed as the difference in cost reduction for CAI patients and a cost-matched comparison population divided by CAI program cost. Results: The excess reduction in per patient asthma-related utilization costs among CAI patients compared to the comparison population was $806 (p = 0.047), $1,253 (p = 0.01) and $1,549 (p = 0.005) between 1 year pre- and 1, 2 and 3 years post-intervention. These yielded adjusted ROI’s of 0.31, 0.78 and 1.37 after 1, 2 and 3 years post-CAI intervention. Conclusions: The reduction in asthma utilization costs of a home visit program by nurse-supervised CHWs exceeds program costs. The findings support the business case for the provision of secondary prevention of home-based asthma services through reimbursement from payers or integration into Accountable Care Organizations (ACOs).
Removal of Gross Artifacts of Transcranial Alternating Current Stimulation in Simultaneous EEG Monitoring †

Transcranial electrical stimulation is a widely used non-invasive brain stimulation approach. To date, EEG has been used to evaluate the effect of transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS), but most studies have been limited to exploring changes in EEG before and after stimulation due to the presence of stimulation artifacts in the EEG data. This paper presents two different algorithms for removing the gross tACS artifact from simultaneous EEG recordings. These give different trade-offs in removal performance, in the amount of data required, and in their suitability for closed loop systems. Superposition of Moving Averages and Adaptive Filtering techniques are investigated, with significant emphasis on verification. We present head phantom testing results for controlled analysis, together with on-person EEG recordings in the time domain, frequency domain, and Event Related Potential (ERP) domain. The results show that EEG during tACS can be recovered free of large scale stimulation artifacts. Previous studies have not quantified the performance of the tACS artifact removal procedures, instead focusing on the removal of second order artifacts such as respiration related oscillations. We focus on the unresolved challenge of removing the first order stimulation artifact, presented with a new multi-stage validation strategy.
Circulating Very Long‐Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study

Background Circulating very‐long‐chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure (HF) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time‐varying levels of the 3 major circulating VLSFAs, lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person‐years among 4249 participants, we identified 1304 cases of incident HF, including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF (P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55–0.81) for 24:0, 0.72 (95% confidence interval, 0.60–0.87) for 22:0 and 0.72 (95% confidence interval, 0.59–0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF, including relevant new risk pathways. Clinical Trial Registration URL: https://www.clinicaltrials. gov. Unique identifier: NCT00005133.
Weighted Tensor Rank-1 Decomposition for Nonlocal Image Denoising

Natural images often contain patches with high similarity. In this paper, to effectively utilize the local and nonlocal self-similarity for low-rank models, we propose a novel weighted tensor rank-1 decomposition method (termed as WTR1) for nonlocal image denoising. Although the low-rank approximation problem has been well studied for matrices, it remains elusive of the theoretical extension to tensors due to the NP-hard tensor decomposition. To tackle this problem, the proposed WTR1 method designs a new efficient CANDECOMP/ PARAFAC (CP) decomposition algorithm and constructs a straightforward low-rank tensor approximation strategy. This is achieved by elegantly manipulating the CP-rank, called intrinsic low-rank tensor approximation. Specifically, the WTR1 method first groups similar patches into a 3D stack and converts the stack into a finite sum of rank-1 products. Then, we deploy the intrinsic low-rank tensor approximation to produce the final denoised image. The proposed WTR1 method can jointly exploit the local and nonlocal self-similarity, thus improving the nonlocal image denoising quality. Experimental results have shown that the proposed WTR1 outperforms several state-of-the-art denoising methods.
Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma

Significance The rising incidence of endometrial cancer in the United States and worldwide can be partially attributed to elevated rates of obesity in the population. Although hysterectomy is an effective treatment for early endometrial cancer, medical interventions are required in advanced cases with metastatic disease or for women wishing to preserve fertility. Here, we present a mouse model with conditional inactivation of the transforming growth factor β (TGFβ) receptor, activin-like kinase 5 (Alk5), that develops estrogen-dependent endometrial adenocarcinoma with distant lung metastases. We anticipate that this mouse will be a useful preclinical model for testing novel therapies for endometrial cancer and for understanding the mechanisms that control endometrial regeneration in the postpartum uterus. The endometrial lining of the uterine cavity is a highly dynamic tissue that is under the continuous control of the ovarian steroid hormones, estrogen and progesterone. Endometrial adenocarcinoma arises from the uncontrolled growth of the endometrial glands, which is typically associated with unopposed estrogen action and frequently occurs in older postmenopausal women. The incidence of endometrial cancer among younger women has been rising due to increasing rates of obesity, a major risk factor for the disease. The transforming growth factor β (TGFβ) family is a highly conserved group of proteins with roles in cellular differentiation, proliferation, and cancer. Inactivating mutations in the genes encoding the TGFβ cell surface receptors (TGFBR1/ALK5 and TGFBR2) have been detected in various human cancers, indicating that a functional TGFβ signaling pathway is required for evading tumorigenesis. In this study, we present a mouse model with conditional inactivation of activin receptor-like kinase 5 (ALK5) in the mouse uterus using progesterone receptor cre (“Alk5 cKO”) that develops endometrial adenocarcinoma with metastasis to the lungs. The cancer and metastatic lung nodules are estrogen dependent and retain estrogen receptor α (ERα) reactivity, but have decreased levels of progesterone receptor (PR) protein. The endometrial tumors develop only in Alk5 cKO mice that are mated to fertile males, indicating that TGFβ-mediated postpartum endometrial repair is critical for endometrial function. Overall, these studies indicate that TGFβ signaling through TGFBR1/ALK5 in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum endometrial regeneration.
Anti-Platelet Antibody Interactions with Fcγ Receptor

In the course of characterizing monoclonal antibod­ ies (mAbs) and their interactions with different blood cell types, it was found in the early 1980s that platelet activa­ tion could be induced by certain mAbs that recognized platelet antigens. 1,2 One of the first activating mAbs to be discovered belongs to a cluster of mAbs (designated CD9) directed to a platelet surface antigen of 24 kDa 1 discovered through screening for acute lymphoblastic leukemia antigens. 3 This initial report was followed by the finding by several groups that a large number of the CD9 mAbs triggered platelet activation. In addition re­ ports describing mAbs against GPIIb/IIIa and other anti­ gens that were also potent platelet activators began to appear in the literature. Summaries of most of these find­ ings were presented at the Leukocyte Typing Workshops III and IV. 4 ' 5
The effects of component‐specific treatment compliance in individually tailored internet‐based treatment

Abstract The objective of this study was to explore the effects of treatment compliance in a guided individually tailored internet‐based treatment (TAIL) in relation to depression and co‐morbid symptoms. Compliance with the homework in the different treatment components in TAIL, each aimed at a specific condition, was rated for 207 participants by independent assessors. Six subgroups (n = 34–131) were constructed consisting of participants with co‐occurring symptoms of worry, panic, social anxiety, stress, insomnia, or pain. For each group, hierarchical regression was used to investigate whether the total sum of compliance points, Overall Compliance, predicted reductions in depression and in condition‐specific symptoms. Also, in each subgroup, it was tested whether working with specific treatment components, Specific Compliance, predicted reduction of the targeted symptoms. Overall Compliance predicted 15% of the reduction in depression symptoms. For participants with worry, panic, social anxiety, stress, or insomnia, Overall Compliance also predicted symptom reductions in that specific condition. Specific Compliance predicted reduction in the targeted symptoms for participants with social anxiety, stress, and insomnia. Specific Compliance with stress and insomnia components also predicted reductions in depression. Our results strengthen the importance of compliance in internet‐based treatments. Because compliance with stress and insomnia components was particularly important for broad symptom reductions, these conditions should not be ignored when treating patients with co‐morbid symptoms.
Design and performance analysis of HARQ for RS-turbo concatenated codes

We study the bit error rate (BER) and mean transmission number (MT) of HARQ for RS-turbo concatenated codes, based on the theoretical analysis. The results show that the code combining of HARQ for RS-turbo could yield reliability improvement. We discuss various schemes of HARQ for the RS-turbo concatenated codes and compare their performance by theoretical analysis and computer simulation. Especially MT and BER of different schemes are simulated over an additive white Gaussian noise (AWGN) channel.
Aromatic amines equilibrium sorptive interaction with synthesized silica based mesoporous MCM-41: Physicochemical evaluation and isotherm modeling

Abstract Present study reports the adsorption of aromatic amine, 4-chloro-o-toluidine (4-COT), onto synthesized mesoporous Mobil Composition of Matter No. 41 (MCM-41) silica nanoparticles, in batch mode. Synthesized MCM-41 was characterized by XRD, BET, FTIR, SEM and TEM analysis. The effects of pH, MCM-41 dose, 4-COT concentration, contact time and temperature were studied, and interaction of 4-COT with the surface of MCM-41 and adsorption process controlling mechanism were investigated. BET analysis of MCM-41 showed 502.77 m2 g–1 of surface area. Kinetic experimental data were well represented by the pseudo-second order kinetic model. Freundlich and Temkin isotherm models well represented the adsorption equilibrium isotherm data.
Four decades of Antarctic Ice Sheet mass balance from 1979–2017

Significance Statement We evaluate the state of the mass balance of the Antarctic Ice Sheet over the last four decades using a comprehensive, precise satellite record and output products from a regional atmospheric climate model to document its impact on sea-level rise. The mass loss is dominated by enhanced glacier flow in areas closest to warm, salty, subsurface circumpolar deep water, including East Antarctica, which has been a major contributor over the entire period. The same sectors are likely to dominate sea-level rise from Antarctica in decades to come as enhanced polar westerlies push more circumpolar deep water toward the glaciers. We use updated drainage inventory, ice thickness, and ice velocity data to calculate the grounding line ice discharge of 176 basins draining the Antarctic Ice Sheet from 1979 to 2017. We compare the results with a surface mass balance model to deduce the ice sheet mass balance. The total mass loss increased from 40 ± 9 Gt/y in 1979–1990 to 50 ± 14 Gt/y in 1989–2000, 166 ± 18 Gt/y in 1999–2009, and 252 ± 26 Gt/y in 2009–2017. In 2009–2017, the mass loss was dominated by the Amundsen/Bellingshausen Sea sectors, in West Antarctica (159 ± 8 Gt/y), Wilkes Land, in East Antarctica (51 ± 13 Gt/y), and West and Northeast Peninsula (42 ± 5 Gt/y). The contribution to sea-level rise from Antarctica averaged 3.6 ± 0.5 mm per decade with a cumulative 14.0 ± 2.0 mm since 1979, including 6.9 ± 0.6 mm from West Antarctica, 4.4 ± 0.9 mm from East Antarctica, and 2.5 ± 0.4 mm from the Peninsula (i.e., East Antarctica is a major participant in the mass loss). During the entire period, the mass loss concentrated in areas closest to warm, salty, subsurface, circumpolar deep water (CDW), that is, consistent with enhanced polar westerlies pushing CDW toward Antarctica to melt its floating ice shelves, destabilize the glaciers, and raise sea level.
Paraoxonase 1 (PON1) Q192R and L55M polymorphisms, lipid profile, lipid peroxidation and lipoprotein-a levels in Turkish patients with pregnancy-related disorders

Abstract The aim of this study was to investigate the role of PON1Q192R and L55M single nucleotide polymorphisms(SNPs) and its association with the maternal levels of lipid parameters in gestational diabetes mellitus(GDM) and preeclampsia(PE). Ninety-nine pregnant with GDM, 97 pregnant with PE and 98 healthy pregnant were included in the study. No statistically significant difference was observed in the alleles or in the genotypes frequencies of SNPs between groups. In GDM patients, total cholesterol was higher in MM genotype of L55M gene (p < .05); Lp(a) were lower in LM genotype of the gene compared to their respective control (p < .05). In PE, HDL-C levels were higher in LM genotype (p < .05); LDL-C levels were lower in MM genotype of the gene compared to their respective control (p < .05). In PE patients, malondialdehyde(MDA) were higher in QQ genotype compared to their respective control (p < .05). Triglyceride levels were higher in PE patients with QR genotype compared with GDM patients with QR genotype (p < .05). Our results indicated that lipid profiles, Lp(a) and MDA levels showed significant differences in GDM and PE pregnants. These findings support the importance of the lipid profile, oxidized lipid and Lp(a) in different genotypes of L55M and Q192R in Turkish pregnant women with PE/GDM suggesting their roles in etiopathogenesis in these pregnancy-related disorders.
Sweet Taste as a Predictor of Dietary Intake: A Systematic Review

Taste is frequently cited as an important factor in food choice, and while a number of studies have attempted to identify relationships between taste function and dietary intake, a systematic review of these studies has been lacking. This review identified studies that examined associations between taste function or taste perception and dietary intake. The purpose was to determine which taste measure was most closely associated with dietary intake in healthy adults. Studies that measured some component of dietary intake, either acutely or longer-term, were eligible for inclusion. Studies were grouped into three categories: those that measured sensitivity (thresholds), intensity, or hedonic responses to sweet stimuli. Sensitivity and intensity studies demonstrated little association with dietary intake measures. Hedonic measurements were more likely to be associated with dietary intake, especially if sweet likers were analyzed separately from sweet dislikers, but the degree of heterogeneity among stimulus concentrations and dietary measures as well as small sample sizes likely obscured more consistent relationships between hedonic evaluation and dietary intake. Due to the potential for within-day and between-day variability in both taste function and dietary intake, future work should explore obtaining more than one taste measurement before comparing results to longer-term dietary assessments and attempts to standardize methods.