Unique Transcriptional Profile of Sustained Ligand-Activated Preconditioning in Pre- and Post-Ischemic Myocardium

BACKGROUND: Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3–5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium. METHODOLOGY/PRINCIPAL FINDINGS: Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated genes in normoxic hearts from SLP mice (≥1.3-fold change, FDR≤5%). Induced genes encoded sarcomeric/contractile proteins (Myh7, Mybpc3,Myom2,Des), natriuretic peptides (Nppa,Nppb) and stress-signaling elements (Csda,Ptgds). Highly repressed genes primarily encoded chemokines (Ccl2,Ccl4,Ccl7,Ccl9,Ccl13,Ccl3l3,Cxcl3), cytokines (Il1b,Il6,Tnf) and other proteins involved in inflammation/immunity (C3,Cd74,Cd83, Cd86,Hla-dbq1,Hla-drb1,Saa1,Selp,Serpina3), together with endoplasmic stress proteins (known: Dnajb1,Herpud1,Socs3; putative: Il6, Gadd45g,Rcan1) and transcriptional controllers (Egr2,Egr3, Fos,Hmox1,Nfkbid). Biological themes modified thus related to inflammation/immunity, together with cellular/cardiovascular movement and development. SLP also modified the transcriptional response to I-R (46 genes uniquely altered post-ischemia), which may influence later infarction/remodeling. This included up-regulated determinants of cellular resistance to oxidant (Mgst3,Gstm1,Gstm2) and other forms of stress (Xirp1,Ankrd1,Clu), and repression of stress-response genes (Hspa1a,Hspd1,Hsp90aa,Hsph1,Serpinh1) and Txnip. CONCLUSIONS: Protection via SLP is associated with transcriptional repression of inflammation/immunity, up-regulation of sarcomeric elements and natriuretic peptides, and modulation of cell stress, growth and development, while conventional protective molecules are unaltered

Platelet Diagnostics:A novel liquid biomarker

The aim of this thesis is to find a novel liquid biomarker for the detection of cancer and to optimize treatment. The first chapter gives an introduction to the oncology biomarker field and focuses on platelets and their role in cancer. In part 1, we evaluate extracellular vesicles (EVs). EVs are small vesicles released by all types of cells, including tumor cells, into the circulation. They carry protein kinases and can be isolated from plasma. We demonstrate that AKT and ERK kinase protein levels in EVs reflect the cellular expression levels and treatment with kinase inhibitors alters their concentration, depending on the clinical response to the drug. Therefore, EVs may provide a promising biomarker biosource for monitoring of treatment responses. Part 2 starts with reviews describing the function and role of platelets in greater depth. Chapter 3 focusses on thrombocytogenesis and several biological processes in which platelets play a role. Furthermore, the RNA processing machineries harboured by platelets are discussed. Both chapter 3 and 4 evaluate the change platelets undergo after being exposed to tumor and its environment. The exchange of biomolecules with tumor cells results in educated platelets, so-called tumor educated platelets (TEPs). TEPs play a role in several hallmarks of cancer and have the ability to respond to systemic alterations making them an interesting biomarker. In chapter 5 the diagnostic potential of platelets is first discussed. We determine their potential by sequencing the RNA of 283 platelet samples, of which 228 are patients with cancer, and 55 are healthy controls. We reach an accuracy of 96%. Furthermore, we are able to pinpoint the location of the primary tumor with an accuracy of 71%. In part 3, our developed thromboSeq platform is taken to the next level. Several potential confounding factors are taken into account such as age and comorbidity. We show that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels. In a validation cohort we apply these algorithms to non-small-cell lung cancer and reach an accuracy of 88% in late stage (n=518) and early-stage 81% accuracy. Finally, in chapter 7 we describe our wet- and dry-lab protocols in detail. This includes platelet RNA isolation, mRNA amplification, and preparation for next-generation sequencing. The dry-lab protocol describes the automated FASTQ file pre-processing to quantified gene counts, quality controls, data normalization and correction, and swarm intelligence-enhanced support vector machine (SVM) algorithm development. Part 4 focuses on central nervous system (CNS) malignancies especially on glioblastoma. Chapter 8 gives an overview of the different liquid biomarkers for diffuse glioma, the most common primary CNS malignancy. In chapter 9 we assess the specificity of the platelet education due to glioblastoma by comparing the RNA profile of TEPs from glioblastoma patients with a neuroinflammatory disease and brain metastasis patients. This results in a detection accuracy of 80%. Secondly, analysis of patients with glioblastoma versus healthy controls in an independent validation series provide a detection accuracy of 95%. Furthermore, we describe the potential value of platelets as a monitoring biomarker for patients with glioma, distinguishing pseudoprogression from real tumor progression. In part 5 thromboSeq is applied to breast cancer diagnostics both as a screening tool in the general population and in a high risk population, BRCA mutated women. In chapter 11 we first apply our technique to an inflammatory condition, multiple sclerosis (MS). Platelet RNA is used as input for the development of a diagnostic MS classifier capable of detecting MS with 80% accuracy in the independent validation series. In the final part we conclude this thesis with a general discussion of the main findings and suggestions for future research

A simulation-based algorithm for solving the resource-assignment problem in satellite telecommunication networks

This paper proposes an heuristic for the scheduling of capacity requests and the periodic assignment of radio resources in geostationary (GEO) satellite networks with star topology, using the Demand Assigned Multiple Access (DAMA) protocol in the link layer, and Multi-Frequency Time Division Multiple Access (MF-TDMA) and Adaptive Coding and Modulation (ACM) in the physical layer.En este trabajo se propone una heurística para la programación de las solicitudes de capacidad y la asignación periódica de los recursos de radio en las redes de satélites geoestacionarios (GEO) con topología en estrella, con la demanda de acceso múltiple de asignación (DAMA) de protocolo en la capa de enlace, y el Multi-Frequency Time Division (Acceso múltiple por MF-TDMA) y codificación y modulación Adaptable (ACM) en la capa física.En aquest treball es proposa una heurística per a la programació de les sol·licituds de capacitat i l'assignació periòdica dels recursos de ràdio en les xarxes de satèl·lits geoestacionaris (GEO) amb topologia en estrella, amb la demanda d'accés múltiple d'assignació (DAMA) de protocol en la capa d'enllaç, i el Multi-Frequency Time Division (Accés múltiple per MF-TDMA) i codificació i modulació Adaptable (ACM) a la capa física

Fast and robust learning by reinforcement signals: explorations in the insect brain

We propose a model for pattern recognition in the insect brain. Departing from a well-known body of knowledge about the insect brain, we investigate which of the potentially present features may be useful to learn input patterns rapidly and in a stable manner. The plasticity underlying pattern recognition is situated in the insect mushroom bodies and requires an error signal to associate the stimulus with a proper response. As a proof of concept, we used our model insect brain to classify the well-known MNIST database of handwritten digits, a popular benchmark for classifiers. We show that the structural organization of the insect brain appears to be suitable for both fast learning of new stimuli and reasonable performance in stationary conditions. Furthermore, it is extremely robust to damage to the brain structures involved in sensory processing. Finally, we suggest that spatiotemporal dynamics can improve the level of confidence in a classification decision. The proposed approach allows testing the effect of hypothesized mechanisms rather than speculating on their benefit for system performance or confidence in its responses

Predicting Precedent: A Psycholinguistic Artificial Intelligence in the Supreme Court

Since the proliferation of analytic methodologies and ‘big data’ in the 1980s, there have been multiple studies claiming to offer consistent predictions for Supreme Court behavior. Political scientists focus on analyzing the ideology of judges, with prediction accuracy as high as 70%. Institutionalists, such as Kaufmann (2019), seek to make predictions on verdicts based on a thorough, qualitative analysis of rules and structures, with predictive accuracy as high as 75%. We argue that a psycholinguistic model utilizing machine learning (SCOTUS_AI) can best predict Court outcomes. Extracting sentiment features from parsed briefs through the Linguistic Inquiry and Word Count (LIWC), our results indicate SCOTUS_AI (AUC = .8087; Top K=.9144) outcompetes traditional analysis in both class-controlled accuracy and range of possible, specific outcomes. Moreover, unlike traditional models, SCOTUS_AI can also predict the procedural outcome of the case as one-hot encoded by remand (AUC=.76). Our findings support a psycholinguistic paradigm of case analysis, suggesting that the framing of arguments is a relatively strong predictor of case results. Finally, we cast predictions for the Supreme Court docket, demonstrating that SCOTUS_AI can be practically deployed in the field for individual cases

Ylikuorman hallinta Diameter-protokollassa liikkuvuuden hallintaa varten

The purpose of this thesis is to develop an overload control solution for Diameter protocol traffic between the MME and HSS in the EPC. The solution is based on using overload information from HSSs and throttling the traffic as needed based on the information. Diameter message prioritization is used to enable ongoing trans- actions to succeed and thus reduce the overload. The performance of the solution is measured with four indicators measuring various aspects of the system's performance. Performance measurements are done via simulations and their results show a clear improvement in system performance when the solution is enabled.Työn tarkoituksena on kehittää ylikuormanhallintaratkaisu neljännen sukupolven matkapuhelinverkkojen ytimen EPC:n MME- ja HSS-verkkoelementtien väliselle Diameter-protokollan yli tapahtuvalle liikenteelle. Hallintaratkaisu perustuu HSS- elementin MME-elementille välittämään tietoon ylikuormasta ja siihen perustuvaan MME-elementin tarpeen vaatiessa tekemään liikenteen rajoittamiseen. Käynnissä olevien transaktioiden lähettämisen onnistuminen varmistetaan käyttämällä Diameter-sanomien priorisointia, mikä vähentää ylikuormaa, kun niitä ei tarvitse lähettää uudestaan. Ratkaisun suorituskykyä mittaamaan on kehitetty neljä eri osa-alueiden suorituskykyä kuvaavaa mittaria. Varsinainen suorituskyvyn mittaus on tehty toteuttamalla ratkaisua simuloiva sovellus ja simulaatioiden tulokset osoittavat järjestelmän suorituskyvyn selkeästi parantuneen ratkaisun ollessa käytössä

A Logistic Regression Model for Biomechanical Risk Classification in Lifting Tasks

Lifting is one of the most potentially harmful activities for work-related musculoskeletal disorders (WMSDs), due to exposure to biomechanical risk. Risk assessment for work activities that involve lifting loads can be performed through the NIOSH (National Institute of Occupational Safety and Health) method, and specifically the Revised NIOSH Lifting Equation (RNLE). Aim of this work is to explore the feasibility of a logistic regression model fed with time and frequency domains features extracted from signals acquired through one inertial measurement unit (IMU) to classify risk classes associated with lifting activities according to the RNLE. Furthermore, an attempt was made to evaluate which are the most discriminating features relating to the risk classes, and to understand which inertial signals and which axis were the most representative. In a simplified scenario, where only two RNLE variables were altered during lifting tasks performed by 14 healthy adults, inertial signals (linear acceleration and angular velocity) acquired using one IMU placed on the subject's sternum during repeated rhythmic lifting tasks were automatically segmented to extract several features in the time and frequency domains. The logistic regression model fed with significant features showed good results to discriminate "risk" and "no risk" NIOSH classes with an accuracy, sensitivity and specificity equal to 82.8%, 84.8% and 80.9%, respectively. This preliminary work indicated that a logistic regression model-fed with specific inertial features extracted by signals acquired using a single IMU sensor placed on the sternum-is able to discriminate risk classes according to the RNLE in a simplified context, and therefore could be a valid tool to assess the biomechanical risk in an automatic way also in more complex conditions (e.g., real working scenarios)

Radio resource management for OFDMA systems under practical considerations.

Orthogonal frequency division multiple access (OFDMA) is used on the downlink of broadband wireless access (BWA) networks such as Worldwide Interoperability for Microwave Access (WiMAX) and Long Term Evolution (LTE) as it is able to offer substantial advantages such as combating channel impairments and supporting higher data rates. Also, by dynamically allocating subcarriers to users, frequency domain diversity as well as multiuser diversity can be effectively exploited so that performance can be greatly improved. The main focus of this thesis is on the development of practical resource allocation schemes for the OFDMA downlink. Imperfect Channel State Information (CSI), the limited capacity of the dedicated link used for CSI feedback, and the presence of a Connection Admission Control (CAC) unit are issues that are considered in this thesis to develop practical schemes. The design of efficient resource allocation schemes heavily depends on the CSI reported from the users to the transmitter. When the CSI is imperfect, a performance degradation is realized. It is therefore necessary to account for the imperfectness of the CSI when assigning radio resources to users. The first part of this thesis considers resource allocation strategies for OFDMA systems, where the transmitter only knows the statistical knowledge of the CSI (SCSI). The approach used shows that resources can be optimally allocated to achieve a performance that is comparable to that achieved when instantaneous CSI (ICSI) is available. The results presented show that the performance difference between the SCSI and ICSI based resource allocation schemes depends on the number of active users present in the cell, the Quality of Service (QoS) constraint, and the signal-to- noise ratio (SNR) per subcarrier. In practical systems only SCSI or CSI that is correlated to a certain extent with the true channel state can be used to perform resource allocation. An approach to quantifying the performance degradation for both cases is presented for the case where only a discrete number of modulation and coding levels are available for adaptive modulation and coding (AMC). Using the CSI estimates and the channel statistics, the approach can be used to perform resource allocation for both cases. It is shown that when a CAC unit is considered, CSI that is correlated with its present state leads to significantly higher values of the system throughput even under high user mobility. Motivated by the comparison between the correlated and statistical based resource allocation schemes, a strategy is then proposed which leads to a good tradeoff between overhead consumption and fairness as well as throughput when the presence of a CAC unit is considered. In OFDMA networks, the design of efficient CAC schemes also relies on the user CSI. The presence of a CAC unit needs to be considered when designing practical resource allocation schemes for BWA networks that support multiple service classes as it can guarantee fairness amongst them. In this thesis, a novel mechanism for CAC is developed which is based on the user channel gains and the cost of each service. This scheme divides the available bandwidth in accordance with a complete partitioning structure which allocates each service class an amount of non-overlapping bandwidth resource. In summary, the research results presented in this thesis contribute to the development of practical radio resource management schemes for BWA networks

Chronology of the development of Active Queue Management algorithms of RED family. Part 1: from 1993 up to 2005

This work is the first part of a large bibliographic review of active queue management algorithms of the Random Early Detection (RED) family, presented in the scientific press from 1993 to 2023. The first part will provide data on algorithms published from 1993 to 2005