Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetics of fusion of the cytoplasmic granules with phagocytic vacuoles in human polymorphonuclear leukocytes. Biochemical and morphological studies

This study on human neutrophils was conducted to measure the kinetics of degranulation of the different cytoplasmic granules into phagocytic vacuoles, and to relate the timing of these events to the burst of respiration that accompanies phagocytosis by these cells. Purified neutrophils were incubated with latex particles opsonized with human immunoglobulin (Ig)G, and phagocytosis was stopped at timed intervals. The cells were examined by electron microscopy to document the sequence of degranulation of the cytoplasmic granules. The azurophil granules and lyosomes were identified by histochemical staining for peroxidase and acid phosphatase, respectively. Phagocytic vacuoles were separated from cell homogenates by floatation on sucrose gradients and assayed for contained lactoferrin, myeloperoxidase, and acid hydrolases. The conclusions drawn from the biochemical and morphological studies were in agreement and indicated: particle uptake and vacuole closure can be completed within 20 s; both the specific and azurophil granules fuse with the phagocytic vacuole much earlier than is generally appreciated, with half-saturation times of 39 s (99% confidence limits, 15-72); oxygen consumption has kinetics similar to those of the fusion of these granules with the phagosome; degranulation of the acid hydrolases beta- glucuronidase, N-acetyl-beta-glucosaminidase (biochemical assays), and acid phosphatase (biochemical assay and electron microscopic cytochemistry) have kinetics of degranulation that are similar to each other but totally different from and much slower than that of myeloperoxidase with half-saturation times of between 354 and 682 s (99% confidence limits, 246-883). This suggests that the acid hydrolases are not co-located with myeloperoxidase in the azurophil granule but are contained in distinct lysosomes, or "tertiary granules".
Precision Electroconvulsive Therapy (PET) project: tackling (cost) effectiveness and patients perspectives

Background. Depression puts a great burden on both patients, relatives and society as a whole. Electroconvulsive therapy (ECT) is regarded as a safe and effective treatment for severe and chronic depressive episodes, even when other interventions such as psychotherapy or psychopharmacology have failed. Despite its superior efficacy, use of ECT for depressed patients is surprisingly low in most European countries as exemplified in a recent Dutch study. This low application rate is possibly due to (1) limited knowledge on the optimal position of ECT in the treatment algorithms, (2) a lack of knowledge on cost-effectiveness, (3) fear for (cognitive) side-effects in patients, relatives and professionals, and (4) the outdated representation of ECT in the media and society at large. Methods. The present study will overcome the aforementioned limitations and setup a large database of merged clinical and research cohorts of ECT-patients (N>1500) and an observational prospective cohort study, in order to analyze aspects of (cost-) effectiveness and side-effects of ECT in retro- and prospective Dutch data. Using these results and together with qualitative information from patients and their relatives, we will disseminate the gained knowledge and develop with a decision-making tool that will guide future patients and their family members referred for ECT. Discussion. Our project will further clarify the position of ECT in treatment algorithms for depression based on scientific data, including data on cost-effectiveness, cognitive side-effects and needs of the patients in the decision-making process. By these means, it will contribute to the development of successful personalized treatment and preventive strategies also in other countries in cooperation with stakeholders such as national and international commissions.
Survey on Security Issues in Cloud Computing and Associated Mitigation Techniques

Computing holds the potential to eliminate the requirements for setting up of high-cost computing infrastructure for IT-based solutions and services that the industry uses. It promises to provide a flexible IT architecture, accessible through internet from lightweight portable devices. This would allow multi-fold increase in the capacity and capabilities of the existing and new software. In a cloud computing environment, the entire data resides over a set of networked resources, enabling the data to be accessed through virtual machines. Since these data-centres may be located in any part of the world beyond the reach and control of users, there are multifarious security and privacy challenges that need to be understood and addressed. Also, one can never deny the possibility of a server breakdown that has been witnessed, rather quite often in the recent times. There are various issues that need to be addressed with respect to security and privacy in a cloud computing environment. This extensive survey paper aims to elaborate and analyze the numerous unresolved issues threatening the cloud computing adoption and diffusion affecting the various stake-holders associated with it. Keywordsas a Service (SaaS), Platform as a Service (PaaS), Infrastructure as a Service (IaaS), Interoperability, Denial of Service (DoS), Distributed Denial of Service (DDoS), Mobile Cloud Computing (MCC), Optical Character Recognition (OCR), Community of Interest (COI).
Phosphorylation-dependent Interactions between ADAM15 Cytoplasmic Domain and Src Family Protein-tyrosine Kinases*

The adamalysins (ADAMs) are transmembrane glycoproteins involved in cell adhesion and proteolytic ectodomain processing of cytokines and adhesion molecules. Many ADAM cytoplasmic domains are proline-rich and have potential phosphorylation sites. We show here that the cytoplasmic domain of ADAM15, metargidin, can interact specifically with Src family protein-tyrosine kinases (PTKs) and the adaptor protein Grb2 in hematopoietic cells (Jurkat, THP-1, U937, and K562 cell lines). Src homology 3 domains from several Src family PTKs including Lck, Fyn, Abl, and Src associate with ADAM15in vitro. Dephosphorylation of cell extracts resulted in decreased association of ADAM15 with Src family PTK SH3 domains, indicating that phosphorylation influences ADAM15 interactions with its binding partners. This was confirmed in vitro for Hck, Lck, and Grb2, which showed enhanced association with tyrosine-phosphorylated glutathione S-transferase-ADAM15 cytoplasmic domain compared with unphosphorylated protein. In contrast, binding of MAD2 to ADAM15 was slightly reduced by phosphorylation of the ADAM. Immunoprecipitation of ADAM15 from Jurkat cells confirmed the association with Lck in vivo, and upon PMA stimulation, the phosphorylation level of ADAM15 was increased. Cotransfection of ADAM15 and Hck showed Hck-dependent phosphorylation of ADAM15in vivo. Hck, and to a lesser extent Lck, phosphorylated the ADAM15 cytoplasmic domain in vitro in immune complex kinase assays. Binding of ADAM15 cytoplasmic domain to Hck and Lck was also shown by Far Western analysis. In contrast to Hck, Lck activity was not required for binding to ADAM15, as shown by treatment of cells with PP1. Deletion and point mutation analysis of the ADAM15 cytoplasmic domain confirmed the importance of the proline-rich motifs for Grb2 and Lck binding and indicated the regulatory nature of Tyr715 and Tyr735. These data demonstrate selective, phosphorylation-dependent interactions of ADAM15 with Src family PTKs and Grb2, which highlight the potential for integration of ADAM functions and cellular signaling.
Language Abnormalities in Alzheimer's Disease Arise from Reduced Informativeness: A Cross-Linguistic Study in English and Persian

INTRODUCTION: This research investigates the psycholinguistic origins of language impairments in Alzheimer's Disease (AD), questioning if these impairments result from language-specific structural disruptions or from a universal deficit in generating meaningful content. METHODS: Cross-linguistic analysis was conducted on language samples from 184 English and 52 Persian speakers, comprising both AD patients and healthy controls, to extract various language features. Furthermore, we introduced a machine learning-based metric, Language Informativeness Index (LII), to quantify informativeness. RESULTS: Indicators of AD in English were found to be highly predictive of AD in Persian, with a 92.3% classification accuracy. Additionally, we found robust correlations between the typical linguistic abnormalities of AD and language emptiness (low LII) across both languages. DISCUSSION: Findings suggest AD linguistics impairments are attributed to a core universal difficulty in generating informative messages. Our approach underscores the importance of incorporating biocultural diversity into research, fostering the development of inclusive diagnostic tools.
A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer Disease

Background: Amyloid beta protein (A-beta) is a treatment target in Alzheimer Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and A{beta}. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on A{beta} metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured A-beta40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, A-beta and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results: From June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF A{beta}40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups. Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.
Response of unconfined turbidity current to relay‐ramp topography: insights from process‐based numerical modelling

This natural‐scale experimental study combines structural modelling of soft‐linked normal‐fault relays with a CFD (computational fluid dynamics) numerical simulation of a range of unconfined turbidity currents overrunning the relay‐system topography. The flow, released from an upslope inlet gate 2000‐m wide and 50‐m to 100‐m high, rapidly expands and adjusts its thickness, velocity and sediment load to the substrate slope of 1.5°. A lower initial sediment concentration or smaller thickness renders the quasi‐steady flow slower and its sediment‐transport capacity lower. A 3D pattern of large interfering Kelvin‐Helmholtz waves causes fluctuations of the local flow velocity magnitude and sediment concentration. Four zones of preferential sediment deposition are recognized: a near‐gate zone of abrupt flow expansion and self‐regulation; a flow‐transverse zone on the counter‐slope of fault footwall edges; a flow‐transverse zone at the fault‐scarp toes and a similar transverse zone near the crest of the hanging wall counter‐slopes. The sand deposited on the counter‐slope tends to be re‐entrained and fed back to the current by a secondary reverse underflow. The spatial extent and sediment accumulation capacity of depozones depend upon the released current volume. The impact of relay system on an overrunning current depends upon the fault separation distance and stage of tectonic evolution. An early‐stage relay system, with small vertical displacement and little overlap of faults, is bypassed by the current with minimum flow disturbance and no pronounced deposition. An advanced‐stage system, with greater fault displacement and overlap, gives a similar hydraulic effect as a single fault segment if the fault separation is small. If the separation is relatively large, the flow tends to be internally redirected sideways from the ramp into the hanging wall synclinal depressions. Since normal‐fault relays are common features in extensional basins, the study bears important implications for turbiditic slope‐fan models and for the spatial sand prediction in subsurface exploration of faulted submarine slopes.
A time-frequency domain approach for pitch-peak picking of noisy speech

This paper presents an improved autocorrelation based algorithm for pitch estimation of noisy speech. The autocorrelation function of the pre-processed noisy speech signal is weighted by an inverse of its variant, circular average magnitude difference function (CAMDF). The inversed CAMDF-weighted autocorrelation function (ICWAF) alone cannot guarantee the de-emphasization of the `non-pitch-peaks'. However, as the dominant pitch-harmonic (DH) of the sinusoidal clean-speech model is expected to be an integer multiple of the pitch, this method concentrates in the effective estimation of the DH using a proposed cosine model of autocorrelation function. Hence, a variable period impulse train with its period being a function of the DH is optimally fitted with the rectified ICWAF to estimate the pitch. The simulation results using the Keele database show that the proposed method claims better accuracy even at a signal to noise ratio (SNR) as low as -10 dB.
Immune dysfunction mediated by the competitive endogenous RNA network in fetal side placental tissue of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets.
Emotional Responses to Computer-Based Training Materials in Education

This paper discusses the results of an experiment that examines how emotional responses influence student satisfaction ratings with computer-based training materials. A comparison between tutorial-based and a simulation-based training showed significant differences in student emotional responses, satisfaction and continuance. The authors caution educators to consider the benefits and limitations of more automated assessment and learning simulation tools versus traditional application-embedded tutorials, as additional layers of training automation may lower student ease-of-use and satisfaction ratings, and ultimately, their interest in the subject.
Generating Multiple Diverse Counterexamples for an EFSM

Model checking is a powerful technique for debugging a system description because it generates a counterexample showing a path of the system that fails a property. Instead of the traditional cycle of find bug – fix bug – re-run model checker, often we would like to study multiple bugs before fixing the model to help isolate the cause of the error and to improve the user’s experience by avoiding iterations of this cycle. However, the set of all counterexamples is often too large to generate or comprehend, and several counterexamples may be caused by the same error. We present a novel method of using a model checker to generate a set of diverse counterexamples to an invariant of an extended finite state machine (EFSM) model. The goal is that each diverse counterexample reveals distinct information about a bug in the model. We use the modelling abstractions of control states and transitions of an EFSM to define whether two counterexamples are equivalent or not. Our method reduces the set of counterexamples on-the-fly and can be used with any LTL model checker.
β‐amyloid precursor protein can be transported independent of any sorting signal to the axonal and dendritic compartment

In neurons, amyloid precursor protein (APP) is localized to the dendritic and axonal compartment. Changes in subcellular localization affect secretase cleavage of APP, altering the generation of Aβ, and presumably also its pathogenic features. It was reported that APP is sorted initially to the axon and transcytosed subsequently to the somatodendritic compartment. This may be carried out by a recessive dendritic sorting signal in the cytoplasmic C‐terminus, possibly the tyrosine based basolateral sorting signal (BaSS), and an axonal sorting motif within the extracellular juxtamembraneous domain. We investigated whether the C‐ or N‐terminal domain of APP contains an independent dendritic or axonal sorting signal. We generated different APP deletion mutants, and produced chimeric proteins of APP and a non‐related Type I transmembrane protein. Quantitative immunocytochemical analyses of transfected primary neurons showed that similar amounts of all APP mutants, lacking either the N‐ or C‐terminus, were transported to the axonal and dendritic compartment. Investigations of the chimeric proteins showed that neither the N‐ nor the C‐terminus of APP functions as independent sorting signal, whereas another tyrosine based dendritic sorting signal was sufficient to prevent axonal entry of APP. This data shows that, under steady state conditions, Heterologously expressed APP is transported equally to axons and dendrites irrespective of any putative sorting signal in its N‐ or C‐terminus. This shows that APP can enter the axon in absence of the initial axonal sorting motif, indicating the existence of an alternative pathway allowing axonal entry of APP. © 2007 Wiley‐Liss, Inc.
Humanin Rescues Cultured Rat Cortical Neurons from NMDA-Induced Toxicity Not by NMDA Receptor

Excitatory neurotoxicity has been implicated in many pathological situations and there is no effective treatment available. Humanin is a 24-aa peptide cloned from the brain of patients with Alzheimer's disease (AD). In the present study, excitatory toxicity was induced by N-methyl-D-aspartate (NMDA) in primarily cultured rat cortical neurons. MTT assessment, lactate dehydrogenase (LDH) release, and calcein staining were employed to evaluate the protective activity of humanin on NMDA induced toxicity. The results suggested that NMDA (100 μmol/L, 2.5 hr) triggered neuronal morphological changes, lactate dehydrogenase (LDH) release (166% of the control), reduction of cell viability (about 50% of the control), and the decrease of living cell density (about 50% of the control). When pretreated with humanin, the toxicity was suppressed. The living cells' density of humanin treated group was similar to that of control. The cell viability was attenuated dose-dependently (IC50 = 0.132 nmol/L). The LDH release was also neutralized in a dose-dependent manner. In addition, the intracellular Ca2+ overloading triggered by NMDA reverted quickly and humanin could not inhibit it. These findings indicate that humanin can rescue cortical neurons from NMDA-induced toxicity in rat but not through interfering with NMDA receptor directly.
Decentralized control of a multiaccess broadcast network

A decentralized control strategy, based on the one step delay sharing information pattern, is proposed for controlling terminal access in a multi-access broadcast network. A Markov chain model of the system is calculated and the infinite time problem of maximizing average throughput is formulated and analyzed using decentralized control theory. Optimal control policies are shown to be extreme and stationary.