Bayesian inference and reinforcement learning models in decision making tasks

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica. Fecha de lectura: 18-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 18-03-201

Bestimmung der lokalen Diskrimination viszeraler Dehnungsreize durch adaptive, selbstkalibrierende Prozeduren

Psychophysikalische Methoden zur Untersuchung der zentralen Verarbeitung interozeptiver Signale sind problematisch: Die Definition des Reizes ist schwierig, und die klassischen Methoden sind auf bewusste Wahrnehmung beschränkt. Im Experiment konnten beide Probleme mit Hilfe eines speziellen Verfahrens gelöst werden. Versuchspersonen waren drei gesunde Frauen und vier gesunde Männer im Alter von 23 bis 42 Jahren. Eine Kolonsonde mit zwei Ballons wurde zur Applikation der Dehnungsreize benutzt. Zunächst wurden die Absolutschwellen bestimmt, danach die Schwellen für die Diskrimination von Reizen, die an verschiedenen Orten appliziert wurden. Die Ergebnisse zeigen, dass (1) kleine Dehnungsreize im Kolon unterschieden werden können, (2) die Unterscheidung durch nachträgliches Feedback der korrekten Antwort verbessert wird und (3) die Unterscheidung interozeptiver Reize nur bei bewusst wahrgenommenen Reizen gelingt, während die Unterscheidung interozeptiver von kutanen Reizen darunter möglich ist

Auswirkungen der Elastizität der Darmwand auf die Wahrnehmung schmerzhafter und nichtschmerzhafter Dehnungsreize bei Gesunden und Patienten mit Irritablem Kolon

In der klinischen Psychophysiologie besteht Uneinigkeit über die relative Bedeutung peripherer gegenüber zentralen und psychologischen Faktoren. Ein Beispiel dafür sind gastrointestinale Schmerzen, wie sie beim Irritablen Kolon (Reizdarmsyndrom) auftreten. Ziel dieser Studie war die Untersuchung peripherer Faktoren bei der Wahrnehmung schmerzhafter und nichtschmerzhafter intraluminaler Dehnungsreize. Es wurden 9 Patienten mit Irritablem Kolon sowie 18 gesunde Kontrollpersonen untersucht. Frühere Ergebnisse einer reduzierten Dehnungstoleranz bei den Patienten konnten repliziert werden; gleichzeitig wurde eine reduzierte mechanische Compliance der Darmwand gefunden. In der Drucktoleranz unterschieden sich Patienten und Gesunde nicht signifikant voneinander. Der Complianceeffekt konnte auch für die kleineren Reize der Wahrnehmungsschwellen bestätigt werden

The genetic history of Italians: new-insights from uniparentally-inherited markers

Genetic differences among human groups can be ascribed both to the broad-scale extents of pre-historical and historical migrations and to the fine-scale impacts of socio-cultural and geographic heterogeneity. In this thesis, the genetic information provided by uniparental markers were exploited to address different aspects of the Italian population history, by combining macro- and micro-geographic investigations at different spatial and temporal scales. To firstly assess the overall Italian variability, Y-chromosome and mtDNA markers were deeply typed in ~900 individuals from continental Italy, Sicily and Sardinia. Sex-biased patterns and contrasting demographic histories were observed for males and females. Differential European and Mediterranean contributions were invoked to explain the paternal genetic sub-structure observed in peninsular Italy, compared to the homogeneous maternal genetic landscape. If Neolithic showed to be one principal determinant of the detected paternal structure, local insights into specific Italian regional contexts highlighted the importance of Post-Neolithic contributions. Among them, migrations from the Balkans (particularly Greece) during late Metal Ages, played a relevant role in the cultural and genetic transitions occurred in Sicily and Southern Italy. On a finer geographic and temporal perspective, the more recent layers of Italian genetic history and some aspects of the gene-culture interaction were assessed by exploring the genetic variability within two “marginal populations”: Arbereshe of Southern Italy and Partecipanza in Northern Italy. The Arbereshe are Albanian-speaking communities settled in Sicily and Calabria since the end of Middle Ages. Despite sharing common genetic and cultural backgrounds, these groups revealed diverging micro-evolutionary histories, implying different founding events and different patterns of cultural isolation and local admixture. Partecipanza is an idiosyncratic institution of Medieval origin aimed at sharing and devolving collective lands. This case-study exemplified that socio-economic stratification within the same population may induce sex-biased genetic structuring and the maintenance of otherwise hidden historical genetic traces

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy - potential clinical relevance

Protein kinase CK2 inhibition has long been considered as an attractive anti-cancer strategy based on the following considerations: CK2 is a pro-survival kinase, it is frequently over-expressed in human tumours and its over-expression correlates with a worse prognosis. Preclinical evidence strongly supports the feasibility of this target and, although dozens of CK2 inhibitors have been described in the literature so far, CX-4945 (silmitasertib) was the first that entered into clinical trials for the treatment of both human haematological and solid tumours. However, kinase inhibitor monotherapies turned out to be effective only in a limited number of malignancies, probably due to the multifaceted causes that underlie them, supporting the emerging view that multi-targeted approaches to treat human tumours could be more effective

Visceral perception of distension stimuli and gut changes in diabetic neuropathy

Wahrnehmungsschwellen und Schmerzschwellen intraluminaler Dehnungsreize im Kolon wurden bei 19 gesunden Kontrollpersonen sowie 19 langjährigen Patienten mit Diabetes mellitus, autonomer und peripherer Neuropathie sowie gastrointestinalen Symptomen gemessen. Weder die Wahrnehmungs- noch die Schmerzschwellen unterschieden sich signifikant voneinander. Bei 44 Prozent der Patienten lag das Delay der Primärkontraktion auf die Dehnung jedoch außerhalb des Bereichs der Kontrollpersonen, und 53 Prozent zeigten abnorme Oszillationen nach dem Ende der Primärkontraktion. Diese Resultate können so interpretiert werden, dass die Hauptstörung der Patienten in den lokalen Mechanismen des enterischen Systems lag, während die afferenten Signalwege ungestört waren. Störungen der efferenten Fasern können jedoch nicht ausgeschlossen werden

Prenatal screening and counseling for genetic disorders

Introduction: The carriers of the same autosomal recessive disorder are usually unaware of onset of the genetic diseases in the children even if screenings are available for many of these disorders. In this paper, we report the experience of the Prenatal Diagnosis Center of AOU Federico II and we discuss the role of the screening for beta-thalassemia (BT), cystic fibrosis (CF) and for other rare genetic disorders. Materials and Methods: We analyzed retrospectively the indication for Prenatal Diagnosis (PD) of all the couples referred to our center from January 1993 to May 2013. We divided our sample into three groups: couples at high risk for BT, for CF and for other rare genetic disorders. Results: From January 1993 to May 2013, we performed 1269 PD for genetic disorders. There are still couples who discovered to be carriers of BT by screening after the birth of the affected child (n=51 (11,3%)); the majority of the people were screened for CF carrier after the birth of an affected child (n=155 (80,7%)) or through the cascade screening (n=28 (14,6%)). Large-scale screenings for rare genetic conditions are not available and people were screened only if they have a positive familial history. Conclusion: Parental screening is available for many severe and rare diseases whose genetic origin is known. The proportion of patients referred for very high-risk indications increased over time with an higher demand for rare disease. An adequate counseling is fundamental to identify women at risk for having affected child. Screening, counseling and PD of genetic diseases is a complex matter and needs for a continuous update

Protein Kinase CK2 Mutants Defective in Substrate Recognition PURIFICATION AND KINETIC ANALYSIS

Five mutants of protein kinase CK2 α subunit in which altogether 14 basic residues were singly to quadruply replaced by alanines (K74A,K75A,K76A,K77A; K79A, R80A,K83A; R191A,R195A,K198A; R228A; and R278A, K279A,R280A) have been purified to near homogeneity either as such or after addition of the recombinant β subunit. By this latter procedure five mutated tetrameric holoenzymes were obtained as judged from their subunit composition, sedimentation coefficient on sucrose gradient ultracentrifugation, and increased activity toward a specific peptide substrate as compared with the isolated α subunits. The kinetic constants and the phosphorylation efficiencies (Vmax/Km) of all the mutants with the parent peptide RRRADDSDDDDD and a series of derivatives, in which individual aspartic acids were replaced by alanines, have been determined. Three mutants, namely K74A,K75A,K76A,K77A; K79A,R80A, K83A; and R191A,R195A,K198A display dramatically lower phosphorylation efficiency and 8-50-fold higher Km values with the parent peptide, symptomatic of reduced attitude to bind the peptide substrate as compared with CK2 wild type. Such differences either disappear or are attenuated if the mutants R191A,R195A, K198A; K79A,R80A,K83A; and K74A,K75A,K76A,K77A are assayed with the peptides RRRADDSADDDD, RRRADDSDDADD, and RRRADDSDDDAA, respectively. In contrast, the phosphorylation efficiencies of the other substituted peptides decrease more markedly with these mutants than with CK2 wild type. These data show that one or more of the basic residues clustered in the 191-198, 79-83, and 74-77 sequences are implicated in the recognition of the acidic determinants at positions +1, +3, and +4/+5, respectively, and that if these residues are mutated, the relevance of the other acidic residues surrounding serine is increased. In contrast the other two mutants, namely R228A and R278A,K279A, R280A, display with all the peptides Vmax values higher than CK2 wild type, counterbalanced however by somewhat higher Kmvalues. It can be concluded from these data that all the five mutations performed are compatible with the reconstitution of tetrameric holoenzyme, but all of them influence the enzymatic efficiency of CK2 to different extents. Although the basic residues mutated in the 74-77, 79-83, and 191-198 sequences are clearly implicated in substrate recognition by interacting with acidic determinants at variable positions downstream from serine, the other basic residues seem to play a more elusive and/or indirect role in catalysis

Patient-specific Monte Carlo-based organ dose estimates in spiral CT via optical 3D body scanning and adaptation of a voxelized phantom dataset: proof-of-principle

: Objective. We present a method for personalized organ dose estimates obtained before the CT exam, via 3D optical body scanning and Monte Carlo (MC) simulations.Approach. A voxelized phantom is derived by adapting a reference phantom to the body size and shape measured with a portable 3D optical scanner, which returns the 3D silhouette of the patient. This was used as an external rigid envelope for incorporating a tailored version of the internal body anatomy derived from a phantom dataset (National Cancer Institute, NIH, USA) matched for gender, age, weight, and height. The proof-of-principle was conducted on adult head phantoms. The Geant4 MC code provided estimates of the organ doses from 3D absorbed dose maps in voxelized body phantom.Main results. We applied this approach for head CT scanning using an anthropomorphic voxelized head phantom derived from 3D optical scans of mannequins. We compared the estimates of head organ doses with those provided by the NCICT3.0 software (NCI, NIH, USA). Head organ doses differed up to 38% using the proposed personalized estimate and MC code, with respect to corresponding estimates calculated for the standard (non-personalized) reference head phantom. Preliminary application of the MC code to chest CT scans is shown. Real-time pre-exam personalized CT dosimetry is envisaged with adoption of a GPU-based fast MC code.Significance. The developed procedure for personalized organ dose estimates before the CT exam, introduces a new approach for realistic description of size and shape of patients via voxelized phantoms specific for each patient