14-3-3 proteins promote synaptic localization of N-methyl d-aspartate receptors (NMDARs) in mouse hippocampal and cortical neurons

One of the core pathogenic mechanisms for schizophrenia is believed to be dysfunction in glutamatergic synaptic transmissions, particularly hypofunction of N-methyl d-aspartate receptors (NMDARs). Previously we showed that 14-3-3 functional knockout mice exhibit schizophrenia-associated behaviors accompanied by reduced synaptic NMDARs in forebrain excitatory neurons. To investigate how 14-3-3 proteins regulate synaptic localization of NMDARs, here we examined changes in levels of synaptic NMDARs upon 14-3-3 inhibition in primary neurons. Expression of 14-3-3 protein inhibitor (difopein) in primary glutamatergic cortical and hippocampal neurons resulted in lower number of synaptic puncta containing NMDARs, including the GluN1, GluN2A, or GluN2B subunits. In heterologous cells, 14-3-3 proteins enhanced surface expression of these NMDAR subunits. Furthermore, we identified that 14-3-3ζ and ε isoforms interact with NMDARs via binding to GluN2A and GluN2B subunits. Taken together, our results demonstrate that 14-3-3 proteins play a critical role in NMDAR synaptic trafficking by promoting surface delivery of NMDAR subunits GluN1, GluN2A, and GluN2B. As NMDAR hypofunctionality is known to act as a convergence point for progression of symptoms of schizophrenia, further studies on these signaling pathways may help understand how dysfunction of 14-3-3 proteins can cause NMDAR hypofunctionality and lead to schizophrenia-associated behaviors.

Place Branding through Resource Integration and Gastro-Cultural Experiences: A Transnational Perspective

Place branding often builds upon gastro-cultural features. Yet, the convergence point between gastro-cultural place identity and the experience on offer could (and should) further benefit from contemporary studies in emerging fields, such as value co-creation and the identity-based approach to place branding. This study contributes towards this direction by examining the practices of relevant actors with main place branding authority. Drawing from their online information and presence, a thematic analysis of relevant brands in Greece and Turkey illustrates that operand and operant resource integration reflect the synergies developed between the gastronomic culture in, for, of the place. Further, actors’ intention to co-create the brand influences and is influenced by the brand. Theoretical and practical insights are derived from this study, which may direct future research and inform policymakers about sustainable, inclusive approaches.

Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs

Neuroblastoma (NB) is one of the most frequently occurring neurogenic extracranial solid cancers in childhood and infancy. Over the years, many pieces of evidence suggested that NB development is controlled by gene expression dysregulation. These unleashed programs that outline NB cancer cells make them highly dependent on specific tuning of gene expression, which can act co-operatively to define the differentiation state, cell identity, and specialized functions. The peculiar regulation is mainly caused by genetic and epigenetic alterations, resulting in the dependency on a small set of key master transcriptional regulators as the convergence point of multiple signalling pathways. In this review, we provide a comprehensive blueprint of transcriptional regulation bearing NB initiation and progression, unveiling the complexity of novel oncogenic and tumour suppressive regulatory networks of this pathology. Furthermore, we underline the significance of multi-target therapies against these hallmarks, showing how novel approaches, together with chemotherapy, surgery, or radiotherapy, can have substantial antineoplastic effects, disrupting a wide variety of tumorigenic pathways through combinations of different treatments.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

A growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or “central hub” for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating “vicious circles” centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast S. cerevisiae, the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG’s). Derepression of these SRG’s is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.

Opinion evolution in society with stubborn agents using Temporal Model for Opinion and Triad Network Formation (TMOTNF)

Information diffusion is an important part of the social network. Information flows between the individuals in the social networks to shape and update their opinions about various topics. The updated opinion values of them further spread the information in the network. The social network is always evolving by nature, leading to the dynamics of the network. Connections keep on changing among the individuals based on the various characteristics of the networks and individuals. Opinions of individuals may again be affected by the changes in the network which leads to dynamics on the network. Therefore, the co-evolving nature of dynamics on/of the network is proposed. Co-evolving Temporal Model for Opinion and Triad Network Formation is modelled to evaluate the opinion convergence. Some fully stubborn agents are chosen in the network to affect opinion evolution, framing society’s opinion. It is also analysed how these agents can divert the whole network towards their opinion values. When temporal modelling is done using all the three conditions, Triadic Closure, Opinion Threshold value and the Page Rank value over the network, the network does not reach consensus at the convergence point. Various individuals with different opinion values still exist.

Building on the Border: Architecture as a Meeting Place

To establish a border signifies defining a fixed point from which to start and to which to refer in order to circumscribe controlled and measured environments. It is not important whether it is a border between states and regions or private and public spaces, because the main effect of the border is to sanction a diversity. This proposal will analyse three case-studies that, starting from antiquity to the contemporary age, have proposed over time different ways of conceiving the border, making architecture the convergence point. The first is the Temple of Diana at Ephesus, a monument created by Greek artists located in Persian territory. It stood on the peninsula of Anatolia, the border land par excellence in the Hellenistic world, a place where the dominant Western cultures of Greece and Persia clashed. The second is Castel Velturno, a border utopia belonging to Prince-Bishop Cristoforo Madruzzo, who deposited his dreams of unification between the North and the South of Christianity which were torn apart by the theological demands addressed during the Council of Trento. Finally, this proposal will examine the contemporary project entitled the Bi-National Community Skyscraper, which proposes a reinterpretation of the walls erected on the border between the USA and Mexico by building a skyscraper on it in which the two communities can meet and merge together.

An Analytical Study of Graphical Password Authentication System

Normally for human psyche it is difficult to recollect text based secret phrase. Text based passwords are not difficult to figure on the grounds that the utilization of general arrangement of numbers, character and unique image, for that reason we carried out the Graphical Password Authentication System. In that we had utilized Image based and Pair based confirmation framework. First and foremost in Imaged based secret key client can pick pixels on that picture as secret key. For each picture just a single pixel is chosen. After choice one pixel change the picture select second pixel from second picture correspondingly clients select three pixels. In pair based secret key, client picks characters from sections and columns all the while from the matrix then, at that point getting that convergence point as a secret key. We have given rearranging choice to exchanging character arrangement it assists with forestalling the shoulder enduring assault, so we have improved security by utilizing PCCP and Imaged based secret key framework which having capacity of shield from the assailant, wafers and so.