Miracle-dz/UniFAR-FTUs huggingface dataset:
A β 1-15/16 as a marker for γ -secretase inhibition in Alzheimer’s disease

Amyloid- β (A β ) producing enzymes are key targets for disease-modifying Alzheimer’s disease (AD) therapies since A β trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that A β 1-15 is produced by concerted β - and α secretase cleavage of amyloid- β protein precursor (A β PP). Here, we test the hypothesis that this pathway is more engaged upon γ -secretase inhibition in humans and cerebrospinal fluid (CSF) levels of A β 1-15/16 represent a biomarker for this effect. Twenty healthy men were treated with placebo (n=5) or the γ -secretase inhibitor semagacestat (100 mg [n=5], 140 mg [n=5], or 280 mg [n=5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for A β 1-15/16 , A β x-38 , A β x-40 , A β x-42 , sA β PP α and sA β PP β . The CSF concentration of A β 1-15/16 showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of A β x-38 , A β x-40 and A β x-42 decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sA β PP α and sA β PP β . Our data shows that CSF levels of A β 1-15/16 increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ -secretase-mediated A β PP-processing.
Understanding the role of the microbiome in COPD: Principles, Challenges and Future Directions

In the past several years, advances in sequencing platforms and bioinformatics have transformed our understanding of the relationship between microbial ecology and human health. Both the normal and diseased lung are host to hundreds of bacterial genera, blurring the lines between “colonization” and “infection”. However whereas in health the respiratory microbiome is determined primarily by the dynamic balance of immigration and elimination, in chronic disease conditions become much more favorable for the reproduction of resident bacteria. Recent studies demonstrate that the microbiota of the COPD lung differ from the healthy lung although significant intra- and inter-subject heterogeneity are still present with variation impacted by factors such as disease stage and inhaled medications. Changes in the relative abundance of specific bacterial taxa during COPD exacerbations have also been noted although further longitudinal analyses are needed to ascertain the malleability and resilience of this ecological system and its role in the occurrence and frequency of exacerbations. Whether patients with a “frequent exacerbator” phenotype possess specific or greater alterations in their airway microbiome that predispose them to recurrent exacerbations as compared to non-frequent exacerbators needs to be determined. While recent data suggest that the presence of bacteria has the potential to influence the host immune response, a key challenge in the next few years will be to continue to move beyond descriptive studies to define the clinical relevance of differences in lung microbiota associated with COPD.
Association of Left Atrial Function with Incident Atypical Atrial Flutter Following Atrial Fibrillation Ablation

, Abstract Background— Symptomatic left atrial (LA) flutter (LAFL) is common following atrial fibrillation (AF) ablation. Objective— To examine the association of baseline LA function with incident LAFL following AF ablation. Methods— The source cohort included 216 patients with cardiac magnetic resonance (CMR) prior to initial AF ablation between 2010 and 2013. Patients who underwent cryoballoon or laser ablation, patients with AF during CMR, and those with suboptimal CMR, or missing follow-up data were excluded. Baseline LA volume and function were assessed by feature-tracking CMR analysis. Results— The final cohort included 119 patients (age 58.9±11 years, 76.5% male, 70.6% paroxysmal AF). During a median follow-up of 421 (interquartile range 235–751) days, 22 (18.5%) patients developed LAFL. Baseline LA volume was similar between the two groups. In contrast, baseline reservoir, conduit and contractile function of the LA were significantly impaired in patients with incident LAFL. Baseline global peak longitudinal atrial strain (PLAS) < 22.65% predicted incident LAFL with 86% sensitivity and 68% specificity (C-statistic 0.76). In a multivariable model adjusting for age, heart failure, and associated with incident LAFL. Coexistence of PLAS<22.65% and linear lesions was associated with 9-fold increased hazard of incident LAFL. Conclusion— Baseline LA function and linear lesions were independently associated with incident LAFL after AF ablation. Linear lesions should be limited to selected cases, especially in patients with impaired LA function. This manuscript examines the association of baseline left atrial functional properties with incident left atrial flutter following after atrial fibrillation ablation. Baseline left atrial functional was impaired in all phases in patients with incident left atrial flutter. After adjusting for potential confounders and linear lesions left atrial function remained independently associated with incident left atrial flutter. Importantly, the co-existence of linear lesions and impaired left atrial function was associated with the highest risk of incident left atrial flutter. Our findings are consistent with the results of the STAR AF II trial, which revealed fewer recurrences in the pulmonary vein isolation versus the pulmonary vein isolation plus substrate modification group, and suggest that linear lesion sets are particularly arrhythmogenic in patients with pre-existing left atrial dysfunction.
VASCULAR MECHANICS, MECHANOBIOLOGY, AND REMODELING 1

Arteries exhibit a remarkable ability to adapt in response to sustained alterations in hemodynamic loading as well as in response to disease, injury, and clinical treatment. A better understanding of such adaptations will be aided greatly by formulating, testing, and refining appropriate theoretical frameworks for modeling the biomechanics and associated mechanobiology. The goal of this brief review is to highlight some recent developments in the use of a constrained mixture theory of arterial growth and remodeling, with particular attention to the requisite constitutive relations, and to highlight future directions of needed research.
Rethinking IT in Construction and Engineering: Organisational Readiness

How could the potential of IT be realised to improve business performance in architecture, construction and engineering organisations? How could organisations unleash the potential of IT to achieve a sustainable competitive advantage? How can organisations migrate from technology to IT-enabled business thinking? Based on the author's twenty years research experience, this book provides a holistic picture of the factors that enable architecture, construction and engineering organisations to explore the potential of IT to improve their businesses and achieve a sustainable competitive advantage. It raises awareness of the importance of the organisational 'soft issues' and the role they play in influencing the outcome of IT investments as well as addressing other complementary enablers, such as knowledge management, learning organisations, maturity models and e-readiness measurements. Real case studies are used throughout the book to illustrate various concepts and to provide the reader with a realistic and practical picture. Rethinking IT in Construction & Engineering is ideal for lecturers and researchers in architecture, construction and engineering as well as professionals at managerial level in industry.
Impact of Prophylactic Conversion to an Extended Infusion Schedule to Prevent Hypersensitivity Reactions in Ovarian Cancer Patients during Carboplatin Retreatment

Objective— Repeated exposure to carboplatin can lead to hypersensitivity reactions during retreatment with carboplatin. This may prevent its further use in platinum-sensitive ovarian cancer patients. At our institution, an increasing proportion of patients are prophylactically converted to an extended schedule of infusion after 8 cycles of carboplatin. We sought to determine whether an incrementally increasing, extended 3-hour infusion of carboplatin was associated with a lower rate of hypersensitivity reactions compared to the standard 30-minute schedule in sequentially treated patients. Methods— We performed a retrospective electronic medical record review of patients with recurrent ovarian cancer retreated with carboplatin at our institution from 01/98–12/08. Results— Seven hundred seventy-seven patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin and met study inclusion criteria. Of these, 117 (17%) developed hypersensitivity reactions during second-line or greater carboplatin-based treatment for recurrent disease. Only 6 (3.4%) of the 174 patients who received the extended schedule developed hypersensitivity reactions (0% grade 4; 1.7% grade 3) compared to 111 (21%) of 533 patients in the standard schedule group (12% grade 4; 77% grade 3). The first hypersensitivity episode occurred after a median of 16 platinum (carboplatin and cisplatin) treatments in the extended group compared to 9 in the standard group. Using the Fisher-exact test, there was an association with a reduced incidence of hypersensitivity reactions with the extended infusion schedule ( P <0.001). Conclusion— Our data suggest appropriate premedication and prophylactic conversion to an extended infusion during carboplatin retreatment may reduce hypersensitivity reactions.
LOCAL AND GLOBAL SOLVABILITY OF SOME PARABOLIC SYSTEMS MODELLING CHEMOTAXIS

Existence of local and global in time solutions for parabolic-elliptic and parabolic systems describing the aggregation of the cellular slime mould by the chemical attraction is studied. In particular, conditions for global in time existence, as well as nite time blow-up are given. Self-similar and radial solutions are also considered.
Model for End-Stage Liver Disease (MELD) Score Measurements on The Daily Basis in Critically Ill Cirrhotic Patients Do Not Provide Additional Prognostic Value

Objective— To determine whether daily measurement of Model for End-Stage Liver Disease (MELD) score adds prognostic value to the initial MELD score in predicting mortality among cirrhotic patients admitted to the intensive care unit (ICU). Methods— We included 830 consecutive cirrhotic patients admitted to a tertiary care ICU between January 1, 2003 and December 31, 2013 who had MELD scores on admission day 1 (MELD-D1). Daily MELD score during the first seven days of ICU admission were retrospectively abstracted. The performances of MELD-D1 to MELD-D7 and changes in MELD score on consecutive days (Δ-MELD) in predicting 90-day mortality were determined using logistic regression. Results— MELD-D1 was an independent predictor of mortality (adjusted OR 1.07, 95% CI, 1.05-1.10; P <.001), with an area under receiver operating characteristic curve (AUC) 0.72. MELD-D2 to MELD-D7 yielded comparable performance to MELD-D1 with a ∼ 10% increase in risk of death per each incremental unit of MELD score (range of ORs 1.09-1.11, P <.001, AUCs 0.68-0.72). Δ-MELD-D2 to Δ-MELD-D7 were not independently associated with mortality ( P >.05 for all) and did not increase the predictive performance (AUCs) when combined with MELD-D2 to MELD-D7. Conclusions— Repeating MELD score assessment during the first seven days after ICU admission does not improve the ability of the initial MELD score for predicting 90-day mortality among cirrhotic patients. Our finding does not support the practice of routine daily measurement of the MELD score.
Targeting of a -kinase-anchoring protein ( a KAP) to sarcoplasmic reticulum and nuclei of skeletal muscle

The sarcoplasmic reticulum (SR) plays a key role in excitation } contraction coupling of skeletal muscle. The SR is composed of two continuous yet heterogeneous membrane compartments, the free or longitudinal SR and cisternal SR. Cisternal SR is made up of free SR membrane, enriched in Ca # + pumps, and junctional SR (jSR) membrane, enriched in ryanodine-sensitive Ca # + -release channels, and contains calsequestrin within its lumen. Protein phosphorylation mediated by the Ca # + } calmodulin-dependent protein kinase II (CaM kinase II) has signiﬁcant, distinct regulatory roles in both Ca # + uptake and Ca # + release. Kinase-anchoring proteins (KAPs) constitute a novel mechanism for achieving cell compartmentalization of eﬀectors in phosphorylation pathways. Here, targeting of a KAP, a CaM kinase II-anchoring protein encoded within the a -CaM kinase II gene, was studied in transgenic skeletal muscle ﬁbres of the adult rat soleus. The transgenes were epitope-tagged versions of a KAP and of a deletion mutant, allowing their speciﬁc immunodetection against the wild-type background. Our results show that a KAP is largely localized at the free SR and thus near the Ca # + pump, a protein that can be modulated by CaM kinase II phosphorylation. Only minor co-localization was observed with the jSR ryanodine-sensitive Ca # + -release channel, which is a potential CaM kinase II target. In non-muscle cells, recombinant a KAP is targeted to endoplasmic reticulum (ER). Both ER and SR targeting requires the N-terminal hydrophobic region of a KAP. An unexpected additional speciﬁc localization that does not require the N-terminus was found in the nucleus, providing a ﬁrst clue of how CaM kinase II can fulﬁl its nuclear functions in skeletal muscle.
Multi-Perspective Ultrasound Imaging Technology of the Breast with Cylindrical Motion of Linear Arrays

In this paper, we propose a multi-perspective ultrasound imaging technology with the cylindrical motion of four piezoelectric micromachined ultrasonic transducer (PMUT) rotatable linear arrays. The transducer is configured in a cross shape vertically on the circle with the length of the arrays parallel to the z axis, roughly perpendicular to the chest wall. The transducers surrounded the breast, which achieves non-invasive detection. The electric rotary table drives the PMUT to perform cylindrical scanning. A breast model with a 2 cm mass in the center and six 1-cm superficial masses were used for the experimental analysis. The detection was carried out in a water tank and the working temperature was constant at 32 °C. The breast volume data were acquired by rotating the probe 90° with a 2° interval, which were 256 × 180 A-scan lines. The optimized segmented dynamic focusing technology was used to improve the image quality and data reconstruction was performed. A total of 256 A-scan lines at a constant angle were recombined and 180 A-scan lines were recombined according to the nth element as a dataset, respectively. Combined with ultrasound imaging algorithms, multi-perspective ultrasound imaging was realized including vertical slices, horizontal slices and 3D imaging. The seven masses were detected and the absolute error of the size was approximately 1 mm where even the image of the injection pinhole could be seen. Furthermore, the breast boundary could be seen clearly from the chest wall to the nipple, so the location of the masses was easier to confirm. Therefore, the validity and feasibility of the data reconstruction method and imaging algorithm were verified. It will be beneficial for doctors to be able to comprehensively observe the pathological tissue.
Probabilistic Power Flow Calculation Using Non-Intrusive Low-Rank Approximation Method

In this paper, a novel non-intrusive probabilistic power flow (PPF) analysis method based on the low-rank approximation (LRA) is proposed, which can accurately and efficiently estimate the probabilistic characteristics (e.g., mean, variance, and probability density function) of the PPF solutions. This method aims at building up a statistically-equivalent surrogate for the PPF solutions through a small number of power flow evaluations. By exploiting the retained tensor-product form of the univariate polynomial basis, a sequential correction-updating scheme is applied, making the total number of unknowns to be linear rather than exponential to the number of random inputs. Consequently, the LRA method is particularly promising for dealing with high-dimensional problems with a large number of random inputs. Numerical studies on the IEEE 39-bus, 118-bus, and 1354-bus systems show that the proposed method can achieve accurate probabilistic characteristics of the PPF solutions with much less computational effort compared to the Monte Carlo simulations. Even compared to the polynomial chaos expansion method, the LRA method can achieve comparable accuracy, while the LRA method is more capable of handling higher-dimensional problems. Moreover, numerical results reveal that the randomness brought about by the renewable energy resources and loads may inevitably affect the feasibility of dispatch/planning schemes.
Linear LINC transmitters using dual-polarized power-combining antennas

It is common practice to use nonlinear, high-efficient power amplifiers to transmit non-constant envelope signals using concepts like LINC (linear amplification using nonlinear components). Traditional systems use a power combiner to reconstruct the non-constant envelope RF signal that is fed into the antenna. In this paper, we will investigate the integration of the power combiner with the radiator, resulting in a LINC power-combining antenna concept. Our novel concept uses two polarizations where the full reconstruction of the signal is done at the receiver side. System-level measurements at 2.45 GHz with 32-QAM signals show that our power-combining antenna concept out-performs traditional LINC implementations.
cAMP Sensor EPAC Proteins and Energy Homeostasis

The pleotropic second messenger cAMP plays a critical role in mediating the effects of various hormones on metabolism. The major intracellular functions of cAMP are transduced by protein kinase A (PKA) and exchange proteins directly activated by cAMP (EPACs). The latter act as guanine nucleotide exchange factors for the RAS-like small G-proteins Rap1 and Rap2. While the role of PKA in regulating energy balance has been extensively studied, EPACs’ impact remains relatively enigmatic. This review summarizes recent genetic and pharmacological studies concerning EPACs’ involvement in glucose homeostasis and energy balance, through regulation of leptin and insulin signaling pathways. Additionally, the development of small molecule EPAC-specific modulators and their therapeutic potential for the treatment of diabetes and obesity are discussed. expression, but show that EPAC2 still plays a role in basal
Sparse Template-Based 6-D Pose Estimation of Metal Parts Using a Monocular Camera

The six-dimensional (6-D) pose estimation of smooth metal parts is a common and important task in intelligent manufacturing. Computer-aided design (CAD)-based monocular vision methods offer more advantages than those offered by other methods. However, they are subject to several drawbacks such as high complexity, low robustness, and unsatisfactory accuracy, which hinder their application in industry. In this paper, a new approach with corresponding practical algorithms is proposed to solve these problems. The proposed approach uses high-level geometric features and the correlation of straight contours, to represent the part. Moreover, it exploits the matched special location points on the geometric features, which are the endpoints of the straight contours, to accurately estimate the 6-D pose. Practical algorithms based on the modification of the existing line-feature descriptors are proposed to implement the approach. The experimental results revealed that the proposed approach and algorithms can achieve higher accuracy and robustness with fewer templates.
A Simplified MPFC With Capacitor Voltage Offset Suppression for the Four-Switch Three-Phase Inverter-Fed PMSM Drive

This paper proposes a simplified model predictive flux control (S-MPFC) for a four-switch three-phase inverter (FSTPI)-fed permanent-magnet-synchronous-motor (PMSM) drive system with the consideration of capacitor voltage offset suppression. A stator flux compensator is introduced to fulfill the capacitor voltage offset suppression. A reference stator flux vector is obtained to represent the reference flux, the reference torque, and the capacitor voltage offset based on the ${\boldsymbol i}_{\boldsymbol d}$ = 0 control mode. Therefore, the flux vector is taken as the only control term in the cost function without any dreary weighting factor tuning work. Moreover, an offset flux error is defined according to the inherent features of the FSTPI, therefore, the optimal voltage vector can be selected in the stationary reference frame using a simple sector division and only one prediction calculation. Experimental results validate the effectiveness of the proposed S-MPFC.
Maximizing Regenerative Braking Energy in Railway Vehicle of Addis Ababa

In this thesis, the problem of maximizing regenerative braking energy is addressed to reduce electrical power consumption of Addis Ababa Light Rail Transit vehicle. The optimization problem is solved using Improved Artificial Bee Colony(IABC) algorithm in case of Ayat-2 to Ayat-1, Mazoria to Chemical Corporation and Meskel Square-1 to Legehar stations and vice versa. The rail road has relatively smaller gradient from Ayat-2 to Ayat-1 station while steepest slope exist between Meskel Square-1 and Legehar Stations. After several simulation tests, the regenerative braking speed profile that satisfies different constrains of railway vehicle is recommended for selected stations. As seen from simulation result, IABC based optimization can restore 25.6383% to 29.4083% total kinetic energy of vehicle in case of Meskel Square-1 to Legehar (2.767 gradient) and Ayat-2 to Ayat-1 (0.00905 gradient) uphill drive braking operation respectively. Significant amount of electrical energy is restored using IABC optimization algorithm as compared to constant braking rate operation. Particularly, 1.1984MJ electrical energy is regenerated using proposed method while 0.6115MJ is recovered using constant braking rate in case of Meskel Square-1 to Legehar uphill drive braking. In downhill drive braking operation, the increase in regenerative braking energy is observed since the tangential component of gravitational force which is exerted on vehicle acts in direction of velocity. Numerically, 3.3669MJ energy is regenerated using IABC algorithm while 3.1074MJ energy is restored by constant braking rate operation in case of 2.767 downhill gradient.
Transforming Growth Factor- b Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2 e Dependent Bladder Cancer Cell Migration and Invasion

Our prior work identi ﬁ ed the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)- b , which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF- b signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-speci ﬁ c survival. Increased expression of TGF- b isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and ablated b e induced migration and invasion. A similar effect when Rictor, a key component, was selectively silenced. Our results suggest that TGF- b can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable most