Effect of color cross-correlated noise on the growth characteristics of tumor cells under immune surveillance

Based on the Michaelis-Menten reaction model with catalytic effects, a more comprehensive one-dimensional stochastic Langevin equation with immune surveillance for a tumor cell growth system is obtained by considering the fluctuations in growth rate and mortality rate. To explore the impact of environmental fluctuations on the growth of tumor cells, the analytical solution of the steady-state probability distribution function of the system is derived using the Liouville equation and Novikov theory, and the influence of noise intensity and correlation intensity on the steady-state probability distributional function are discussed. The results show that the three extreme values of the steady-state probability distribution function exhibit a structure of two peaks and one valley. Variations of the noise intensity, cross-correlation intensity and correlation time can modulate the probability distribution of the number of tumor cells, which provides theoretical guidance for determining treatment plans in clinical treatment. Furthermore, the increase of noise intensity will inhibit the growth of tumor cells when the number of tumor cells is relatively small, while the increase in noise intensity will further promote the growth of tumor cells when the number of tumor cells is relatively large. The color cross-correlated strength and cross-correlated time between noise also have a certain impact on tumor cell proliferation. The results help people understand the growth kinetics of tumor cells, which can a provide theoretical basis for clinical research on tumor cell growth

Hippocampus

The hippocampus is a bicortical structure with extensive fiber connections with multiple brain regions. It is involved in several functions, such as learning, memory, attention, emotion, and more. This book covers various aspects of the hippocampus including cytoarchitecture, functions, diseases, and treatment. It highlights the most advanced findings in research on the hippocampus. It discusses circuits, pattern formation process of grid cells, and zinc dynamics of the hippocampus. The book also addresses the tau pathology and circRNAs related to Alzheimer’s disease and potential treatment strategies. It is a useful resource for general readers, students, and researchers

A study of SNARE-mediated autophagosome clearance using fluorescence lifetime microscopy

Cell survival requires the turnover of toxic cellular material and recycling of biomolecules in low nutrient conditions. An efficient degradation system is therefore essential for disease prevention and its dysfunction has been linked to both neurodegeneration and oncogenesis. Bulk degradation is accomplished through the collection of cytoplasmic material in a unique sequestration vesicle, which forms de novo and subsequently deposits cargo in the lysosome for degradation. This process, known as autophagy, therefore requires membrane fusion between the autophagosomal vesicle and the lysosome. SNARE proteins mediate membrane fusion events and therefore their careful regulation ensures the proper organisation of the membrane trafficking network. The SNARE proteins governing autophagosome clearance have been identified as syntaxin 17, SNAP29 and VAMP8 and SNARE assembly appears to be positively regulated by VPS33A. This well established model of SNARE-mediated autophagosome clearance has not, however, been demonstrated within the spatiotemporal framework of the cell and little is known about how VPS33A modulates SNARE function. The research presented in this thesis therefore aims to determine the applicability of the proposed SNARE model within the cellular environment and to investigate the regulatory mechanisms controlling syntaxin 17 function. To accomplish this, carefully validated fluorescence colocalisation and time-resolved fluorescence lifetime imaging techniques were primarily employed. The limitations of these techniques were also considered for data interpretation and a novel prototype SPAD array technology, designed for high-speed time-correlated single photon counting, was trialled for widefield FLIM-FRET. FLIM-FRET revealed that VAMP8 has been incorrectly assigned as the dominant autophagosomal R-SNARE and VPS33A studies evidence a multi-modal regulation of Stx17 that diverges from other studied syntaxin family modulation mechanisms. A new model of SNAREmediated autophagosome clearance is therefore proposed, where syntaxin 17 engages with SNAP29 and VAMP7 to drive membrane fusion with the endolysosome in a manner governed by VPS33A and dependent on the phosphorylation status of syntaxin 17

Protein Structure

Since the dawn of recorded history, and probably even before, men and women have been grasping at the mechanisms by which they themselves exist. Only relatively recently, did this grasp yield anything of substance, and only within the last several decades did the proteins play a pivotal role in this existence. In this expose on the topic of protein structure some of the current issues in this scientific field are discussed. The aim is that a non-expert can gain some appreciation for the intricacies involved, and in the current state of affairs. The expert meanwhile, we hope, can gain a deeper understanding of the topic

Functionally Relevant Macromolecular Interactions of Disordered Proteins

Disordered proteins are relatively recent newcomers in protein science. They were first described in detail by Wright and Dyson, in their J. Mol. Biol. paper in 1999. First, it was generally thought for more than a decade that disordered proteins or disordered parts of proteins have different amino acid compositions than folded proteins, and various prediction methods were developed based on this principle. These methods were suitable for distinguishing between the disordered (unstructured) and structured proteins known at that time. In addition, they could predict the site where a folded protein binds to the disordered part of a protein, shaping the latter into a well-defined 3D structure. Recently, however, evidence has emerged for a new type of disordered protein family whose members can undergo coupled folding and binding without the involvement of any folded proteins. Instead, they interact with each other, stabilizing their structure via “mutual synergistic folding” and, surprisingly, they exhibit the same residue composition as the folded protein. Increasingly more examples have been found where disordered proteins interact with non-protein macromolecules, adding to the already large variety of protein–protein interactions. There is also a very new phenomenon when proteins are involved in phase separation, which can represent a weak but functionally important macromolecular interaction. These phenomena are presented and discussed in the chapters of this book

Pharmacological BACE1 inhibitor treatment during early progression of β-amyloid pathology maximizes therapeutic efficacy

Alzheimer’s disease (AD) is a chronic neurodegenerative disease of the central nervous system (CNS) characterized by progressive cognitive decline. AD is the most common cause of all dementia cases worldwide, and as a result of demographic aging the number of affected individuals grows at an alarming rate. The amyloid hypothesis of Alzheimer’s disease (AD) emphasizes amyloid-β peptide (Aβ) as primary cause of the disease, with toxic effects on synapses leading to cognitive decline and memory impairments. Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) as the rate-limiting enzyme of amyloidogenic processing of amyloid precursor protein (APP), is one of the prime drug targets for the treatment of AD. However, despite the development of potent and selective small-molecule BACE1 inhibitors, so far all human clinical trials have failed to rescue the cognitive decline in AD patients. Recent findings indicate that treatment has to be commenced before AD symptoms arise, since in symptomatic patients β amyloid deposition has already reached a plateau. Moreover, several studies have described dose-dependent adverse effects in animal models. Therefore, it is a central requirement to develop a treatment strategy that is therapeutically effective and at the same time avoids excessive interference with physiological function of BACE1. In this study, transgenic AD mice were treated at an early stage of β amyloid pathology with the potent, blood brain barrier penetrating BACE1 inhibitor NB-360. Longitudinal in vivo two-photon imaging was performed to repeatedly monitor individual amyloid plaques, presynaptic boutons and axonal dystrophies in living mice. In APPPS1 mice pharmacological BACE1 inhibition fails to revert but significantly reduces the progressive amyloid deposition and mitigates presynaptic pathology. Notably, the data show that plaque seed formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. These results imply, that preventive BACE1 inhibitor treatment is required to achieve therapeutic efficacy. For clinical therapy, to exploit the particular susceptibility of plaque formation to BACE1 inhibition, a dosage has to be empirically determined that effectively halts formation of new plaques rather than aiming at halting plaque growth. This strategy might optimally balance potential mechanism-based adverse effects and efficacious reduction of β amyloid deposition.Morbus Alzheimer ist eine chronische neurodegenerative Erkrankung des zentralen Nervensystems und äußert sich in progressivem Verlust kognitiver Funktionen und Gedächtnisleistung. Die Erkrankung ist die weltweit häufigste Ursache für Demenz und aufgrund demografischer Alterung in den Industrie¬ländern, nimmt die Zahl der Alzheimer Patienten stetig zu. Der Amyloid-Kaskaden-Hypothese zufolge, wird die Alzheimer Erkrankung durch pathologische Akkumulation und Aggregation des Aβ-Peptids (Aβ) ausgelöst. Aβ wird durch sequentielle enzymatische Spaltung des Amyloid-Vorläufer-proteins APP produziert. Die β-Sekretase BACE1 initiiert den ersten Schritt dieses sogenannten amyloiden Prozessierungswegs und ist somit eines der aussichtsreichsten Wirkstoffziele zur Senkung des Aβ-Spiegels. Im Verlauf der letzten Jahre wurden sehr wirksame und zugleich selektive BACE1 Inhibitoren hergestellt, doch bislang sind klinische Studien daran gescheitert, den progressiven Gedächtnisverlust aufzuhalten. Neueste Erkenntnisse weisen darauf hin, dass die Behandlung bereits vor dem Auftreten der ersten Symptome begonnen werden muss, da in symptomatischen Patienten die Ablagerung von Aβ in den meisten Fällen bereits abgeschlossen ist. Hinzu kommt, dass in den letzten Jahren vermehrt negative Begleiterscheinungen der Behandlung mit BACE1 Inhibitoren in Mäusen bekannt geworden sind. Die entscheidende Herausforderung ist somit, eine Behandlungsstrategie zu entwickeln, welche einerseits die physiologische Funktion von BACE1 nicht zu stark beeinträchtigt, aber zugleich therapeutische Effizienz gewährleistet. In der vorliegenden Studie wurden transgene Alzheimer Mäuse in einem frühen Stadium der β amyloiden Pathologie mit dem potenten BACE1 Inhibitor NB-360 behandelt. Mittels chronischer in vivo Mikroskopie konnten einzelne β amyloide Plaques, präsynaptische Boutons und axonale Dystrophien in lebenden Mäusen verfolgt werden. Die Behandlung erbrachte zwar keinen Rückgang der Aβ Ablagerung, konnte jedoch deren Fortschreiten verringern, sowie die progressive axonale Pathologie abschwächen. Insbesondere zeigten unsere Daten, dass die BACE1 Inhibitor Behandlung einen wesentlich größeren Einfluss auf die Bildung neuer β amyloider Plaques, als auf deren Wachstum hatte. Diese Ergebnisse weisen darauf hin, dass die Behandlung mit BACE1 Inhibitoren präventiv erfolgen muss. Für die klinische Anwendung könnte man sich die besondere Anfälligkeit der Neubildung von Plaques zu Nutze machen und über empirische Versuche einen Dosisbereich bestimmen, welcher ausreicht, die Neubildung von Plaques zu unterdrücken. Diese Strategie könnte zu einer ausgewogenen Behandlung führen, welche die progressive Aβ Ablagerung verzögert und gleichermaßen das Auftreten von Nebenwirkungen verhindert

Development and validation of kinase activity reporters for the dynamic study of cell response modalities by microscopy

Necroptosis is defined as a caspase-independent programmed cell death and relies on a signaling pathway involving two serine-threonine kinases: Receptor-Interacting Protein Kinase 1 and 3 (RIPK1 and RIPK3) and the pseudo-kinase Mixed-Lineage Kinase Like (MLKL). Activation of Extracellular signal-Regulated Kinases 1 and 2 (ERK1/2) was reported to be involved in different modes of programmed cell death. It is now accepted that the regulation of the duration, magnitude and subcellular compartmentalization of ERK1/2 activity by specific spatio-temporal regulators is interpreted by the cell towards cell fate determination. ERK1/2 inhibition delays TNFα-induced necroptosis in L929 cells in a dose dependent manner but did not block it, providing arguments for a pro-necrotic function of ERK1/2. In this context, a compartmentalized biphasic phosphorylation of ERK1/2 was observed. Our results indicate a RIPK1-dependent phosphorylation of ERK1/2. Owing to the importance of ERK1/2 spatio-temporal dynamics in determining cellular responses, we developed a new reporter of ERK2 localization named ERK2-LOC. We observed a transient translocation of ERK2 when necroptosis was triggered in L929 upon TNFα stimulation, followed by progressive ERK2 accumulation in the nucleus. ERK1/2 activities were monitored during necroptosis using a FRET-based kinase biosensor for ERK1/2 (ERK1/2-ACT). Using ERK1/2-ACT, a dedicated spatio-temporal signature of ERK1/2 activity was recorded during necroptosis. Finally, to correlate ERK1/2 activity code with necroptosis occurrence, we also engineered a first generation of FRET biosensors to report on both RIPK1 and RIPK3 activities during necroptosis

Production of gelatin methacrylate printable bioinks for cancer cells studies

In questo elaborato è presentato uno studio volto alla produzione di hydrogels semisintetici, a base di gelatina di origine animale funzionalizzata con gruppi metacrilici, utilizzabili come inchiostri biocompatibili per la stampa con tecnologie di micro estrusione di matrici tridimensionali, ottimizzate nella forma e nelle dimensioni per studi sul comportamento di cellule tumorali di Neuroblastoma

The Fuzziness in Molecular, Supramolecular, and Systems Chemistry

Fuzzy Logic is a good model for the human ability to compute words. It is based on the theory of fuzzy set. A fuzzy set is different from a classical set because it breaks the Law of the Excluded Middle. In fact, an item may belong to a fuzzy set and its complement at the same time and with the same or different degree of membership. The degree of membership of an item in a fuzzy set can be any real number included between 0 and 1. This property enables us to deal with all those statements of which truths are a matter of degree. Fuzzy logic plays a relevant role in the field of Artificial Intelligence because it enables decision-making in complex situations, where there are many intertwined variables involved. Traditionally, fuzzy logic is implemented through software on a computer or, even better, through analog electronic circuits. Recently, the idea of using molecules and chemical reactions to process fuzzy logic has been promoted. In fact, the molecular word is fuzzy in its essence. The overlapping of quantum states, on the one hand, and the conformational heterogeneity of large molecules, on the other, enable context-specific functions to emerge in response to changing environmental conditions. Moreover, analog input–output relationships, involving not only electrical but also other physical and chemical variables can be exploited to build fuzzy logic systems. The development of “fuzzy chemical systems” is tracing a new path in the field of artificial intelligence. This new path shows that artificially intelligent systems can be implemented not only through software and electronic circuits but also through solutions of properly chosen chemical compounds. The design of chemical artificial intelligent systems and chemical robots promises to have a significant impact on science, medicine, economy, security, and wellbeing. Therefore, it is my great pleasure to announce a Special Issue of Molecules entitled “The Fuzziness in Molecular, Supramolecular, and Systems Chemistry.” All researchers who experience the Fuzziness of the molecular world or use Fuzzy logic to understand Chemical Complex Systems will be interested in this book