Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells

Intensive community care services for children and young people in psychiatric crisis: an expert opinion.

BACKGROUND: Children and young people's (CYP) mental health is worsening, and an increasing number are seeking psychiatric and mental health care. Whilst many CYPs with low-to-medium levels of psychiatric distress can be treated in outpatient services, CYPs in crisis often require inpatient hospital treatment. Although necessary in many cases, inpatient care can be distressing for CYPs and their families. Amongst other things, inpatient stays often isolate CYPs from their support networks and disrupt their education. In response to such limitations, and in order to effectively support CYPs with complex mental health needs, intensive community-based treatment models, which are known in this paper as intensive community care services (ICCS), have been developed. Although ICCS have been developed in a number of settings, there is, at present, little to no consensus of what ICCS entails. METHODS: A group of child and adolescent mental health clinicians, researchers and academics convened in London in January 2023. They met to discuss and agree upon the minimum requirements of ICCS. The discussion was semi-structured and used the Dartmouth Assertive Community Treatment Fidelity Scale as a framework. Following the meeting, the agreed features of ICCS, as described in this paper, were written up. RESULTS: ICCS was defined as a service which provides treatment primarily outside of hospital in community settings such as the school or home. Alongside this, ICCS should provide at least some out-of-hours support, and a minimum of 90% of CYPs should be supported at least twice per week. The maximum caseload should be approximately 5 clients per full time equivalent (FTE), and the minimum number of staff for an ICCS team should be 4 FTE. The group also confirmed the importance of supporting CYPs engagement with their communities and the need to remain flexible in treatment provision. Finally, the importance of robust evaluation utilising tools including the Children's Global Assessment Scale were agreed. CONCLUSIONS: This paper presents the agreed minimum requirements of intensive community-based psychiatric care. Using the parameters laid out herein, clinicians, academics, and related colleagues working in ICCS should seek to further develop the evidence base for this treatment model

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Modelling a magnetic dipole's position and motion using magnetometry

209 σ.Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Συστήματα Αυτοματισμού”Σκοπός της παρούσας Μεταπτυχιακής εργασίας, είναι η επίλυση του προβλήματος που αφορά στον εντοπισμό της θέσης και του προσανατολισμού ενός ή περισσοτέρων διπόλων βάσει της έντασης του μαγνητικού πεδίου που δημιουργούν γύρω τους. Αφορμή για την ανάπτυξη της, υπήρξε η χρήση αισθητήρων πεδίου σε εφαρμογές εντοπισμού μαγνητικών μαζών. Θεωρώντας ένα πλοίο ως ένα μαγνητικό δίπολο, μετρήσεις της έντασης του μαγνητικού πεδίου σε κάποιο συγκεκριμένο σύνορο γύρω του, θα μπορούσαν να χρησιμοποιηθούν για τον προσδιορισμό της θέσης και του προσανατολισμού του, καθώς αυτό κινείται και μεταβάλλει το μαγνητικό πεδίο γύρω του. Ο προσδιορισμός του κατάλληλου αριθμού αισθητήρων που απαιτούνται για τον εντοπισμό του, αποτελεί επίσης αντικείμενο αυτής της εργασίας. Για την επίλυση αυτού του προβλήματος, αρχικά μελετάται η δημιουργία του μαγνητικού πεδίου γύρω από ένα δίπολο, που αποτελεί το ευθύ πρόβλημα. Η μοντελοποίηση γίνεται με χρήση της μεθόδου των πεπερασμένων στοιχείων, και συγκεκριμένα του λογισμικού πεπερασμένων στοιχείων ANSYS, και των εξισώσεων Maxwell. Η επίλυση του μοντέλου, δίνει ως αποτέλεσμα τις τιμές της έντασης του μαγνητικού πεδίου σε διάφορα σημεία ενδιαφέροντος, τα οποία μπορούν να ταυτιστούν με τα σημεία στα οποία τοποθετούνται οι αισθητήρες πεδίου. Για την επίλυση του αντιστρόφου προβλήματος, δηλαδή του προσδιορισμού της θέσης και του προσανατολισμού των διπόλων βάσει των τιμών της έντασης του μαγνητικού πεδίου γύρω του, επιλέγεται η μέθοδος των νευρωνικών δικτύων. Αναπτύσσονται και μελετώνται, διάφορες αρχιτεκτονικές νευρωνικών δικτύων προσοτροφοδότησης, τα οποία χρησιμοποιούν ως δεδομένα εισόδου για την εκπαίδευση τους, την επαλήθευση τους και τον έλεγχο τους, τις τιμές της έντασης του μαγνητικού πεδίου και ως δεδομένα εξόδου τις καρτεσιανές συντεταγμένες του κέντρου των διπόλων και τη γωνία προσανατολισμού τους, όπως αυτά προκύπτουν από τη χρήση της μεθόδου των πεπερασμένων στοιχείων. Τα νευρωνικά δίκτυα δημιουργούνται και εκπαιδεύονται στο MATLAB, με τη χρήση κατάλληλων αλγορίθμων και ελέγχονται ως προς την απόδοση τους. Στόχος της εργασίας, είναι η αποτελεσματικότητα της επιλογής των νευρωνικών δικτύων ως μέθοδο για την επίλυση του συγκεκριμένου προβλήματος, με γνώμονα την ελαχιστοποίηση του αριθμού των αισθητήρων για τη μέτρηση του μαγνητικού πεδίου.A ship, magnetized in the earth’s magnetic field, creates a local magnetic perturbation that is its magnetic signature. As a result, a ship could be considered as a giant magnetic dipole that changes the magnetic field intensity of its surrounding area. Magnetometers that are based on magnetic materials and magnetic effects, such as the magneto-resistance effect, the magneto-impedance effect and inductive techniques could be used as an alternative measurement technique for applications such as navigation and monitoring or detection of magnetic masses. A crucial issue, regarding this approach for naval vessel monitoring, is the difficulty in defining the appropriate number of magnetic sensors needed and their respective configuration, in order to predict accurately the position and the orientation of a magnetic mass through the measured magnetic field intensities on a specific boundary. Magnetic field intensities’ measurements could be used as input in inverse engineering techniques in order to solve this problem. Neural networks had been widely used in inverse problems solving. Data observed are transformed to model parameters, through a neural network that is trained with this kind of data. In the present thesis, the design and the evaluation of different types of neural networks, as an approach of detecting the position and orientation of a number of dipoles through the measured magnetic field intensities on a specific boundary, are analyzed. Different networks' architectures have been considered, mainly regarding the number of samples included in the datasets, the number of hidden layers, the number of neurons at each layer and the size of the input vector, which corresponds to the values of the magnetic field intensity measured by a number of sensors placed at the boundary. The input datasets needed, derive from the solution of the forward problem with ANSYS finite element software.Αικατερίνη Ε. Σκούτ

Modulatory profiling identifies mechanisms of small molecule-induced cell death

Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones

Data Package 2

FPKM expression values from RNA-seq using parental DU-145 prostate cancer cells and clonal cell lines derived from the parental line with resistance to erastin-induced ferroptosis. Sample nomenclature is as follows: "2.5E-2" means this resistant line was produced using a selective pressure of 2.5uM Erastin, and was the second clone evaluated at that concentration. The column titles map to one parental and five resistant clonal lines tested: DU-145 (parental, sensitive), 2.5E-1, 2.5E-2, 2.5E-3, 2.5E-5, and 2.6E-23 (all resistant). Fold changes were calculated using the ratio of each resistant line/parental (column directly to the right of each resistant line). Average fold changes (resistant/parental, column M) and average ΔFPKM (resistant - parental, column N) for each gene across all resistant lines were calculated. For these experiments, only genes with FPKM > 0.1 in the DU-145 condition and FPKM ≥ 1 for all other conditions were evaluated

Data from: Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis

Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc− is implicated in numerous pathologies. Pharmacological agents that inhibit system xc− activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system xc−. RNA sequencing revealed that inhibition of cystine–glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1, providing a pharmacodynamic marker for system xc− inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc− function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis