Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog

During development of the vertebrate neural tube, cells acquire their positional identity from not only the spatial level of the Sonic Hedgehog signaling gradient, but also the temporal duration

Σχέσεις Ρωμαϊκού Κράτους & Χριστιανικής Εκκλησίας τον Δ΄Αιώνα

Ύστερα από συζητήσεις που διεξήχθησαν κατά τη διάρκεια της διδασκαλίας του μαθήματος του Σεβασμιώτατου Γρηγορίου Παπαθωμά, οδηγήθηκα και με παρότρυνση του Σεβασμιότατου να πραγματευθώ ένα θέμα ως Διπλωματική εργασία, του οποίου το κύριο πεδίο έρευνας, θα αφορούσε τις διαμορφωθείσες σχέσεις μεταξύ Χριστιανικής Εκκλησίας και Ρωμαϊκού Κράτους, το 4ο αιώνα. Ένα αιώνα που αποτελεί ορόσημο και για την Αυτοκρατορία και για τη Χριστιανική Εκκλησία, αφού οι από το τέλος του 3ου αιώνα προσπάθειες για ανακοπή της πτωτικής και διαβρωτικής πορείας της Αυτοκρατορίας σε σημείου που να οδηγείται στην πλήρη αποσύνθεση και κατάρρευση, οδήγησαν στο πρώτο τέταρτο του 4ου αιώνος σε άρδην μεταβολή της φυσιογνωμίας της Αυτοκρατορίας και της λειτουργίας της. Μεταβολές που ώθησαν και μια νέα ανάπτυξη σχέσεων μεταξύ της Αυτοκρατορίας και της Χριστιανικής Εκκλησίας, ανατρέποντας πλήρως όλα τα προηγούμενα δεδομένα που είχαν επικρατήσει, με την Εκκλησία πλέον να εντάσσεται σε ένα πλαίσιο που θα αποτελέσει σημείο καμπής για την εξέλιξη της αφού πλέον από την παρανομία και τους διωγμούς, όχι μόνο είναι ελεύθερη να ασκεί τα καθήκοντά της, αλλά σταδιακά ευνοείται από την Πολιτεία και προστατεύεται έως σημείου στο τέλος του 4ου αιώνα να επικρατήσει ως η μόνη επίσημη Θρησκεία του Κράτους, θέτοντας η Πολιτεία όλες τις άλλες θρησκείες όχι απλώς στο περιθώριο, αλλά και στην απαγόρευση κάθε δραστηριότητας τους. Θα καταβληθεί προσπάθεια να απαντηθούν ερωτήματα, όπως τη μορφή έλαβε και διαμόρφωνε η Χριστιανική Εκκλησία κατά την περίοδο του 4ου αιώνος. Πως αντιλαμβανόταν το Κράτος τη θέση του έναντι της Χριστιανικής Εκκλησίας και τι έπραττε στο πεδίο της συνύπαρξης αυτής και αντίστροφα. Ποιος ήταν, εάν υπήρχε, ο κυρίαρχος τύπος που χαρακτήριζε τη σχέση μεταξύ του Κράτους και της Χριστιανικής Εκκλησίας και ιδιαίτερα του Αυτοκράτορος και αυτής. Η εργασία εκτός από την Εισαγωγή, θα περιλαμβάνει το Πρώτο Κεφάλαιο το οποίο θα αναφέρεται στην εποχή πριν την αναγνώριση της Χριστιανικής Εκκλησίας, ώστε να διαπιστώσουμε τις συνθήκες που επικρατούσαν στη σχέση του Ρωμαϊκού Κράτους και της Εκκλησίας και τη μορφή της Εκκλησίας τότε, ώστε να πραγματοποιήσουμε μια σύγκριση με την κύρια εποχή που αναφερόμαστε και να αντιληφθούμε και να κατανοήσουμε με τον καλύτερο δυνατό τρόπο τις μεγάλες αλλαγές που ελάμβαναν χώρα και στις σχέσεις μεταξύ Χριστιανικής Εκκλησίας και Ρωμαϊκού Κράτους, αλλά και τις μεταβολές που συνέβαιναν και στην Εκκλησία. Στη συνέχεια στο Δεύτερο Κεφάλαιο που θα αναφέρετε στις Απαρχές των σχέσεων της Χριστιανικής Εκκλησίας με την Πολιτεία κατά τους Ρωμαϊκούς χρόνους επί της Βασιλείας του Μεγάλου Κωνσταντίνου έως και της Βασιλείας του Θεοδοσίου του Α΄. Περίοδος κατά την οποία η Χριστιανική Εκκλησία από διωκόμενη και παράνομη από το Ρωμαϊκό Κράτος, αναγνωρίζεται ως Εκκλησία που μπορεί να δραστηριοποιείται και να ασκεί τα καθήκοντα της τα λατρευτικά ελεύθερα. Παράλληλα παρατηρούμε μια υπέρ το δέον ευνοϊκή στάση από τη Ρωμαϊκή Πολιτεία έναντι της Χριστιανικής Εκκλησίας, με αποκορύφωμα την αναγνώριση ως της μόνης νόμιμης και επίσημης Εκκλησίας στην επικράτεια της Ρωμαϊκής Αυτοκρατορίας. Στο Τρίτο Κεφάλαιο θα προβάλουμε θέσεις των Διαφωτιστών για την Αυτοκρατορία και θα αντιπαρατεθούμε με αυτές και θα κατατεθεί το Ιδεολογικό Πρόταγμα που αναπτύχθηκε στο Ρωμαϊκό Κράτος της Ανατολής. Στο τέλος θα παρατεθεί ένα Κεφάλαιο το οποίο θα περιλαμβάνει τα Συμπεράσματα από την έρευνα και μια επισκόπηση όλων όσων έχουν παρατεθεί. Η εργασία τέλος θα ολοκληρωθεί με ένα επίνειο – επίλογο.The purpose of this work is to present the data and events that took place during two important periods for Hellenism and the Christian church, two periods in which significant and even world-historical changes took place that directly related to the course and future of both Hellenism and the Christian church of the united in the first period we are looking at and then the Christian church of the East in the geographical area of southern Greece. , where a national liberation revolution took place. The first period refers to the period of the 4th century in which the declining world power of the Time, the Roman Empire, after successive civil wars, stabilizes, acquiring a leadership that sees that, the survival and development of the empire, lies in the realization of groundbreaking changes and orientations. Some points of the new course and the exemption from introversions and "barrels" of the past, were the declaration of freedom of religion in the empire and the freedom of all those who reside in it to freely exercise their worship duties and to manifest their faith, without prohibitions, persecutions and convictions, operating illegally and treating the state as an enemy. This act benefited the empire from unnecessary and cost-effective persecution. At the same time this act with the focus of the empire in its Eastern part in which populations abound with Greek and Christian element, gradually and with the favor of the emperors, Hellenism and Christianity emerge as dominant factors of the empire and features of its ideology and worldview in a unique combination with each other. The second period concerns the 19th century in which in the main Greek area, after a long enslavement, Hellenism decides to rebel and be liberated. This decision as well as its implementation that led to new data in these areas with the final creation of a New Greek State independent, which in itself causes a new reality in which Greek society and the church are placed in the areas of the new State. The task outline includes Insert, both chapters, and the summary. In the first chapter we refer to the period of the 4th century and the developments that took place in it in relation to the bodies that concern us and in the second chapter we will refer to the period from the beginning of the revolution of 1821 to the present day and to the corresponding events that affected and affected relations between Church and State. In the Summary we will try to make a comparative view of the two periods to make a decision on the realities of these two critical and catalytic periods

A Comprehensive Review of the Cardiovascular Protective Properties of Silibinin/Silymarin: A New Kid on the Block

Silibinin/silymarin has been used in herbal medicine for thousands of years and it is well-known for its hepato-protective properties. The present comprehensive literature review aimed to critically summarize the pharmacological properties of silymarin extract and its main ingredient silibinin in relation to classical cardiovascular risk factors (e.g., diabetes mellitus, etc.). We also assessed their potential protective and/or therapeutic application in cardiovascular diseases (CVDs), based on experimental and clinical studies. Pre-clinical studies including in vitro tests or animal models have predominantly implicated the following effects of silymarin and its constituents: (1) antioxidant, (2) hypolipidemic, (3) hypoglycemic, (4) anti-hypertensive and (5) cardioprotective. On the other hand, a direct amelioration of atherosclerosis and endothelial dysfunction after silymarin administration seems weak based on scarce data. In clinical trials, the most important findings are improved (1) glycemic and (2) lipid profiles in patients with type 2 diabetes mellitus and/or hyperlipidemia, while (3) the anti-hypertensive effects of silibinin/silymarin seem very modest. Finally, the changes in clinical endpoints are not robust enough to draw a firm conclusion. There are significant limitations in clinical trial design, including the great variety in doses and cohorts, the underlying conditions, the small sample sizes, the short duration and the absence of pharmacokinetic/pharmacodynamic tests prior to study commitment. More data from well-designed and high-quality pre-clinical and clinical studies are required to firmly establish the clinical efficacy of silibinin/silymarin and its possible therapeutic application in cardiovascular diseases

Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog.

Morphogens are secreted signalling molecules that act in a graded manner to control the pattern of cellular differentiation in developing tissues. An example is Sonic hedgehog (Shh), which acts in several developing vertebrate tissues, including the central nervous system, to provide positional information during embryonic patterning. Here we address how Shh signalling assigns the positional identities of distinct neuronal subtype progenitors throughout the ventral neural tube. Assays of intracellular signal transduction and gene expression indicate that the duration as well as level of signalling is critical for morphogen interpretation. Progenitors of the ventral neuronal subtypes are established sequentially, with progressively more ventral identities requiring correspondingly higher levels and longer periods of Shh signalling. Moreover, cells remain sensitive to changes in Shh signalling for an extended time, reverting to antecedent identities if signalling levels fall below a threshold. Thus, the duration of signalling is important not only for the assignment but also for the refinement and maintenance of positional identity. Together the data suggest a dynamic model for ventral neural tube patterning in which positional information corresponds to the time integral of Shh signalling. This suggests an alternative to conventional models of morphogen action that rely solely on the level of signalling

Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube

The secreted ligand Sonic Hedgehog (Shh) organizes the pattern of cellular differentiation in the ventral neural tube. For the five neuronal subtypes, increasing levels and durations of Shh signaling direct progenitors to progressively more ventral identities. Here we demonstrate that this mode of action is not applicable to the generation of the most ventral cell type, the nonneuronal floor plate (FP). In chick and mouse embryos, FP specification involves a biphasic response to Shh signaling that controls the dynamic expression of key transcription factors. During gastrulation and early somitogenesis, FP induction depends on high levels of Shh signaling. Subsequently, however, prospective FP cells become refractory to Shh signaling, and this is a prerequisite for the elaboration of their identity. This prompts a revision to the model of graded Shh signaling in the neural tube, and provides insight into how the dynamics of morphogen signaling are deployed to extend the patterning capacity of a single ligand. In addition, we provide evidence supporting a common scheme for FP specification by Shh signaling that reconciles mechanisms of FP development in teleosts and amniotes

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Gene Regulatory Logic for Reading the Sonic Hedgehog Signaling Gradient in the Vertebrate Neural Tube

Secreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research