The Bar in America: The Role of Elitism in a Liberal Democracy

Part I of this Note argues that liberal democracy, the free market, and science have contributed to the increasing atomization of American society. When each person and her views are glorified, universal standards of good become undermined, values become relative, and a sense of community becomes evanescent. Part II argues that individualism is incapable of accounting for the commonweal and therefore is inherently amoral because morality is concerned largely with determining when an individual\u27s will should be subservient to the will of others. Part III considers the nature of elitism and equality and attributes the demise of elitist institutions in America to the rise of individualism and egalitarianism. When liberal democracy, bolstered by the free market and science, overturned discriminatory institutions of the past, it rightfully eliminated the immoral excesses of institutional elitism. Unfortunately, liberal democracy did so without discretion, discrediting not only the immoral aspects of elitism but its desirable aspects as well. The ethic of service to others that is the most sacred quality of the legal profession, therefore, is threatened. Moreover, the destruction of elitist institutions has left a vacuum that has not been filled. The country, therefore, needs a force that promotes a sense of community and embodies an ethos of service to others. Finally, Part IV argues that the Bar is a distinctive public calling which engenders special access to, and control over, the instruments of government and a unique ability to affect private rights. By virtue of this elite position, the Bar has a moral responsibility to serve the public. The Bar should fulfill its duties by countering the atomizing influences of liberal democracy, the free market, and science through the example of service to others

Introduction of Hypermatrix and Operator Notation into a Discrete Mathematics Simulation Model of Malignant Tumour Response to Therapeutic Schemes In Vivo. Some Operator Properties

The tremendous rate of accumulation of experimental and clinical knowledge pertaining to cancer dictates the development of a theoretical framework for the meaningful integration of such knowledge at all levels of biocomplexity. In this context our research group has developed and partly validated a number of spatiotemporal simulation models of in vivo tumour growth and in particular tumour response to several therapeutic schemes. Most of the modeling modules have been based on discrete mathematics and therefore have been formulated in terms of rather complex algorithms (e.g. in pseudocode and actual computer code). However, such lengthy algorithmic descriptions, although sufficient from the mathematical point of view, may render it difficult for an interested reader to readily identify the sequence of the very basic simulation operations that lie at the heart of the entire model. In order to both alleviate this problem and at the same time provide a bridge to symbolic mathematics, we propose the introduction of the notion of hypermatrix in conjunction with that of a discrete operator into the already developed models. Using a radiotherapy response simulation example we demonstrate how the entire model can be considered as the sequential application of a number of discrete operators to a hypermatrix corresponding to the dynamics of the anatomic area of interest. Subsequently, we investigate the operators’ commutativity and outline the “summarize and jump” strategy aiming at efficiently and realistically address multilevel biological problems such as cancer. In order to clarify the actual effect of the composite discrete operator we present further simulation results which are in agreement with the outcome of the clinical study RTOG 83–02, thus strengthening the reliability of the model developed

Interplay between the endogenous opioid system and proteasome complex: Beyond signaling

Intracellular signaling mechanisms underlying the opioid system regulation of nociception, neurotransmitters release, stress responses, depression, and the modulation of reward circuitry have been investigated from different points of view. The presence of the ubiquitin proteasome system (UPS) in the synaptic terminations suggest a potential role of ubiquitin-dependent mechanisms in the control of the membrane occupancy by G protein-coupled receptors (GPCRs), including those belonging to the opioid family. In this review, we focused our attention on the role played by the ubiquitination processes and by UPS in the modulation of opioid receptor signaling and in pathological conditions involving the endogenous opioid system. The collective evidence here reported highlights the potential usefulness of proteasome inhibitors in neuropathic pain, addictive behavior, and analgesia since these molecules can reduce pain behavioral signs, heroin self-administration, and the development of morphine analgesic tolerance. Moreover, the complex mechanisms involved in the effects induced by opioid agonists binding to their receptors include the ubiquitination process as a post-translational modification which plays a relevant role in receptor trafficking and degradation. Hence, UPS modulation may offer novel opportunities to control the balance between therapeutic versus adverse effects evoked by opioid receptor activation, thus, representing a promising druggable target

The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms

Oxaliplatin-induced neuropathy (OXAIN) is a major adverse effect of this antineoplastic drug, widely used in the treatment of colorectal cancer. Although its molecular mechanisms remain poorly understood, recent evidence suggest that maladaptive neuroplasticity and oxidative stress may participate to the development of this neuropathy. Given the role played on protein remodeling by ubiquitin–proteasome system (UPS) in response to oxidative stress and in neuropathic pain, we investigated whether oxaliplatin might cause alterations in the UPS-mediated degradation pathway, in order to identify new pharmacological tools useful in OXAIN. In a rat model of OXAIN (2.4 mg kg−1 i.p., daily for 10 days), a significant increase in chymotrypsin-(β5) like activity of the constitutive proteasome 26S was observed in the thalamus (TH) and somatosensory cortex (SSCx). In addition, the selective up-regulation of β5 and LMP7 (β5i) subunit gene expression was assessed in the SSCx. Furthermore, this study revealed that oprozomib, a selective β5 subunit proteasome inhibitor, is able to normalize the spinal prodynorphin gene expression upregulation induced by oxaliplatin, as well as to revert mechanical allodynia and thermal hyperalgesia observed in oxaliplatin-treated rats. These results underline the relevant role of UPS in the OXAIN and suggest new pharmacological targets to counteract this severe adverse effect. This preclinical study reveals the involvement of the proteasome in the oxaliplatin-induced neuropathy and adds useful information to better understand the molecular mechanism underlying this pain condition. Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy

Early-life nicotine or cotinine exposure produces long-lasting sleep alterations and downregulation of hippocampal corticosteroid receptors in adult mice

Early-life exposure to environmental toxins like tobacco can permanently re-program body structure and function. Here, we investigated the long-term effects on mouse adult sleep phenotype exerted by early-life exposure to nicotine or to its principal metabolite, cotinine. Moreover, we investigated whether these effects occurred together with a reprogramming of the activity of the hippocampus, a key structure to coordinate the hormonal stress response. Adult male mice born from dams subjected to nicotine (NIC), cotinine (COT) or vehicle (CTRL) treatment in drinking water were implanted with electrodes for sleep recordings. NIC and COT mice spent significantly more time awake than CTRL mice at the transition between the rest (light) and the activity (dark) period. NIC and COT mice showed hippocampal glucocorticoid receptor (GR) downregulation compared to CTRL mice, and NIC mice also showed hippocampal mineralocorticoid receptor downregulation. Hippocampal GR expression significantly and inversely correlated with the amount of wakefulness at the light-to-dark transition, while no changes in DNA methylation were found. We demonstrated that early-life exposure to nicotine (and cotinine) concomitantly entails long-lasting reprogramming of hippocampal activity and sleep phenotype suggesting that the adult sleep phenotype may be modulated by events that occurred during that critical period of life

Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine-related drug that may damage the dopaminergic nigrostriatal system. To investigate the mechanisms that sustain this toxic effect and ascertain their sex-dependence, we evaluated in the nigrostriatal system of MDMA-treated (4 × 20 mg/kg, 2 h apart) male and female mice the activity of superoxide dismutase (SOD), the gene expression of SOD type 1 and 2, together with SOD1/2 co-localization with tyrosine hydroxylase (TH)-positive neurons. In the same mice and brain areas, activity of glutathione peroxidase (GPx) and of β2/β5 subunits of the ubiquitin-proteasome system (UPS) were also evaluated. After MDMA, SOD1 increased in striatal TH-positive terminals, but not nigral neurons, of males and females, while SOD2 increased in striatal TH-positive terminals and nigral neurons of males only. Moreover, after MDMA, SOD1 gene expression increased in the midbrain of males and females, whereas SOD2 increased only in males. Finally, MDMA increased the SOD activity in the midbrain of females, without affecting GPx activity, decreased the β2/β5 activities in the striatum of males and the β2 activity in the midbrain of females. These results suggest that the mechanisms of MDMA-induced neurotoxic effects are sex-dependent and dopaminergic neurons of males could be more sensitive to SOD2- and UPS-mediated toxic effects

Exploiting Clinical Trial Data Drastically Narrows the Window of Possible Solutions to the Problem of Clinical Adaptation of a Multiscale Cancer Model

The development of computational models for simulating tumor growth and response to treatment has gained significant momentum during the last few decades. At the dawn of the era of personalized medicine, providing insight into complex mechanisms involved in cancer and contributing to patient-specific therapy optimization constitute particularly inspiring pursuits. The in silico oncology community is facing the great challenge of effectively translating simulation models into clinical practice, which presupposes a thorough sensitivity analysis, adaptation and validation process based on real clinical data. In this paper, the behavior of a clinically-oriented, multiscale model of solid tumor response to chemotherapy is investigated, using the paradigm of nephroblastoma response to preoperative chemotherapy in the context of the SIOP/GPOH clinical trial. A sorting of the model's parameters according to the magnitude of their effect on the output has unveiled the relative importance of the corresponding biological mechanisms; major impact on the result of therapy is credited to the oxygenation and nutrient availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. The effect of a number of parameter combinations on the extent of chemotherapy-induced tumor shrinkage and on the tumor's growth rate are discussed. A real clinical case of nephroblastoma has served as a proof of principle study case, demonstrating the basics of an ongoing clinical adaptation and validation process. By using clinical data in conjunction with plausible values of model parameters, an excellent fit of the model to the available medical data of the selected nephroblastoma case has been achieved, in terms of both volume reduction and histological constitution of the tumor. In this context, the exploitation of multiscale clinical data drastically narrows the window of possible solutions to the clinical adaptation problem

CONTRIBUTION OF EMPIRICAL METHODS AND SATELLITE DATA USE FOR ESTIMATING DAILY REFERENCE EVAPOTRANSPIRATION

Στην παρούσα εργασία χρησιμοποιούνται επίγεια και δορυφορικά μετεωρολογικά δεδομένα του έτους 2014 από την περιοχή της Βοιωτίας. Τα επίγεια δεδομένα προέρχονται από τον αυτόματο αγρομετεωρολογικό σταθμό (ΑΑΣ) μέτρησης της εξατμισοδιαπνοής αναφοράς (ΕΤο) του Γεωπονικού Πανεπιστημίου Αθηνών (ΓΠΑ). Τα μετεωρολογικά δορυφορικά δεδομένα (SAT) αντιστοιχούν σε πολύγωνο 0.25οΧ0.25ο εντός του οποίου λειτουργεί και ο ΑΑΣ. Χρησιμοποιώντας τα επίγεια αλλά και τα δορυφορικά δεδομένα, υπολογίσθηκε η ΕΤο με τη μέθοδο FAO-56 PM, αλλά και με τρεις εμπειρικές μεθόδους (Copais, Valiantzas και Hargreaves-Samani) και πραγματοποιήθηκαν συγκρίσεις με σκοπό να αξιολογηθεί η αξιοπιστία των μοντέλων. Ως βάση των συγκρίσεων υιοθετήθηκε η μέθοδος FAO-56 PM με χρήση επίγειων δεδομένων. Από την εργασία προκύπτει ότι τόσο για τα επίγεια όσο και για τα δορυφορικά δεδομένα η μέθοδος Copais δίνει τις καλύτερες εκτιμήσεις ακολουθούμενη από την μέθοδο Valiantzas και με σοβαρή υπερεκτίμηση η Hargreaves-Samani. In the present study we used ground and satellite meteorological data of the year 2014 from the region of Viotia-Greece. The ground data were obtained from the automatic grass reference evapotranspiration station (AAS) of the Agricultural University of Athens. The satellite data (SAT) cover an area of 0,25ο x 0,25ο that includes the AAS. By using the ground and the satellite data we calculated the reference evapotranspiration, ΕΤο, with the method FAO-56 PM and with three empirical methods (Copais, Valiantzas and Hargreaves-Samani). The FAO-56 PM was used as a benchmark method to compare and validate the performances of the others methods. The results show that for both the ground and the satellite data, Copais method is the most accurate followed by Valiantzas and Hargreaves-Samani, indicated by serious overestimation