Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been supported by tests that are mostly non-specific and, sometimes, insensitive. Recent laboratory developments have led to a variety of tests that rely on a disease-specific mechanism. One test, the CSF RT-QuIC (Real-Time Quaking-Induced Conversion)

Since their original identification, prions have represented enigmatic agents that defy the classical concept of genetic inheritance. For almost four decades, the high-resolution structure of PrPSc, the infectious and misfolded counterpart of the cellular prion protein (PrPC), has remained elusive, mostly due to technical challenges posed by its high insolubility and aggregation propensity. As a result

Mammalian prion or PrPSc is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein or PrPC. Sialylation of the prion protein, a terminal modification of N-linked glycans, was discovered more than 30 years ago, yet the role of sialylation in prion pathogenesis is not well understood. This chapter summarizes current knowledge

The protein-only hypothesis predicts that infectious mammalian prions are composed solely of PrPSc, a misfolded conformer of the normal prion protein, PrPC. However, to date, all wild type protein-only PrPSc preparations lack significant levels of prion infectivity. Using a systemic biochemical approach, our laboratory isolated and identified two different endogenous cofactor molecules, RNA (Deleault

Prions are a self-propagating misfolded conformation of a cellular protein. Prions are found in several eukaryotic organisms with mammalian prion diseases encompassing a wide range of disorders. The first recognized prion disease, the transmissible spongiform encephalopathies (TSEs), affect several species including humans. Alzheimer's disease, synucleinopathies, and tauopathies share a similar mechanism

Transmissible spongiform encephalopathies or prion diseases describe a number of different human disorders that differ in their clinical phenotypes, which are nonetheless united by their transmissible nature and common pathology. Clinical variation in the absence of a conventional infectious agent is believed to be encoded by different conformations of the misfolded prion protein. This misfolded protein

Prions are unique agents that challenge the molecular biology dogma by transmitting information on the protein level. They cause neurodegenerative diseases that lack of any cure or treatment called transmissible spongiform encephalopathies. The function of the normal form of the prion protein, the exact mechanism of prion propagation between species as well as at the cellular level and neuron degeneration

The transmission of prions between species is typically an inefficient process due to the species barrier, which represents incompatibility between prion seed and substrate molecules. Bank voles (Myodes glareolus) are an exception to this rule, as they are susceptible to a diverse range of prion strains from many different animal species. In particular, bank voles can be efficiently infected with most

Misfolding and aggregation of proteins play a central role in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's and Lewy Body diseases, Frontotemporal Lobar Degeneration and prion diseases. Increasing evidence supports the view that Aβ and tau, which are the two main molecular players in AD, share with the prion protein several “prion-like” features

The ordered assembly of a small number of proteins into amyloid filaments is central to age-related neurodegenerative diseases. Tau is the most commonly affected of these proteins. In sporadic diseases, assemblies of tau form in a stochastic manner in certain brain regions, from where they appear to spread in a deterministic way, giving rise to disease symptoms. Over the past decade, multiple lines

The misfolding, aggregation, and deposition of specific proteins is the key hallmark of most progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). ALS is characterized by the rapid and progressive degenerations of motor neurons in the spinal cord and motor cortex, resulting in paralysis of those who suffer from it. Pathologically

Neurodegenerative disorders are invariably associated with intra- or extra-cellular deposition of aggregates composed of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Emerging evidence suggests that the circulating soluble species of these misfolded proteins (usually referred as oligomers) could play a major

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), atypical parkinsonisms, frontotemporal dementia (FTLD) and prion diseases are characterized by the accumulation of misfolded proteins in the central nervous system (CNS). Although the cause for the initiation of protein aggregation is not well understood, these aggregates are disease-specific. For instance

Here we describe the principles of protein surgery and its application to the molecular design for regulating the protein conformation. We initially describe the Poincare duality that defines the basis of complementarity in the time-dependent geometrical space. Next we introduce the theory of protein surgery consisting of “dissection” and “suture,” which correspond to differentiation and integration

During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational

Being responsible for more than 90% of cellular functions, protein molecules are workhorses in all the life forms. In order to cater for such a high demand, proteins have evolved to adopt diverse structures that allow them to perform myriad of functions. Beginning with the genetically directed amino acid sequence, the classical understanding of protein function involves adoption of hierarchically complex

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder thought to be caused by predisposing high-risk genes that may be altered during the early development by environmental factors. The impact of maternal challenges during pregnancy on the prevalence of ASD has been widely studied in clinical and animal studies. Here, we review some clinical and pre-clinical evidence that links environmental

Directed stabilization of globular proteins via substitution of a minimal number of amino acid residues is one of the most complicated experimental tasks. In this work, we have successfully used algorithms for the evaluation of intrinsic disorder predisposition (such as PONDR® FIT and IsUnstruct) as tools for searching for the weakened regions in structured globular proteins. We have shown that the

G protein-coupled receptors (GPCRs) and Nuclear Receptors (NRs) are two signaling machineries that are involved in major physiological processes and, as a consequence, in a substantial number of diseases. Therefore, they actually represent two major targets for drugs with potential applications in almost all public health issues. Full exploitation of these targets for therapeutic purposes nevertheless

The double face of nickel, being both a toxic element for living organisms and a necessary metal for enzymatic reactions, forces nickel-dependent organisms to develop regulatory networks in order to tightly control the intracellular Ni(II) ion quota, avoiding the occurrence of a free Ni(II) pool and overcoming the natural scarcity of this metal ion in the environment. Among nickel-dependent enzymes

Autism spectrum disorder (ASD) is a set of pervasive neurodevelopmental disorders. The causation is multigenic in most cases, which makes it difficult to model the condition in vitro. Advances in pluripotent stem cell technology has made it possible to generate in vitro models of human brain development. Induced pluripotent stem cells (iPSCs) can be generated from somatic cells and have the ability

A substantive volume of research on autism spectrum disorder (ASD) has emerged in recent years adding to our understanding of the etiopathological process. Preclinical models in mice and rats have been highly instrumental in modeling and dissecting the contributions of a multitude of known genetic and environmental risk factors. However, the translation of preclinical data into suitable drug targets

Correlation and association analyses are one of the most widely used statistical methods in research fields, including microbiome and integrative multiomics studies. Correlation and association have two implications: dependence and co-occurrence. Microbiome data are structured as phylogenetic tree and have several unique characteristics, including high dimensionality, compositionality, sparsity with

The cellular recycling process of macroautophagy, which is the mechanism by which cellular material is delivered to lysosomes via double membraned vesicles called autophagosomes, is intimately connected to programmed cell death pathways, especially apoptosis. In this article, I discuss some underlying mechanisms and their implications for improving cancer therapy and propose that the approaches that

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired development and by abnormal function in regards to social interaction, communication and restricted, repetitive behavior. It affects approximately 1% of the worldwide population. Like other psychiatric disorders the diagnosis is based on observation of, and interview with the patient and next of kin, and diagnostic

Highly complex endophenotypes and underlying molecular mechanisms have prevented effective diagnosis and treatment of autism spectrum disorder. Despite extensive studies to identify relevant biosignatures, no biomarker and therapeutic targets are available in the current clinical practice. While our current knowledge is still largely incomplete, -omics technology and machine learning-based big data

Altered sensory processing and perception has been one of the characteristics of autism spectrum disorder (ASD). In this chapter, we review the neural underpinnings of sensory abnormalities of ASD by examining the literature on clinical, behavioral and neurobiological evidence that underlies the main patterns of sensory integration function and dysfunction. Furthermore, neural differences in anatomy

The development of new approaches for the clinical management of autism spectrum disorder (ASD) can only be realized through a better understanding of the neurobiological changes associated with ASD. One strategy for gaining deeper insight into the neurobiological mechanisms associated with ASD is to identify converging pathogenic processes associated with human idiopathic clinicopathology that are

Liquid-liquid phase separation (LLPS) brings together functionally related proteins through the intrinsic biophysics of proteins in a process that is driven by reducing free energy and maximizing entropy. The process of LLPS allows proteins to form structures, termed membrane-less organelles. These diverse, dynamic organelles are active in a wide range of processes in the nucleus, cytoplasm, mitochondria

Autophagy is a cellular housekeeping and quality control mechanism that is essential for homeostasis and survival. By virtue of this role, any perturbations to the flow of this process in cardiac or vascular cells can elicit harmful effects on the cardiovascular system, and subsequently affect whole organismal health. In this chapter, we summarize the preclinical evidence supporting the role of autophagy

Neurodevelopmental impairment remains a significant morbidity in former very low birth weight premature infants. There is increasing evidence the microbiome affects neurodevelopment but mechanistic causes are largely unknown. There are many factors which affect the developing microbiome in infants including mode of delivery, feeding, medications, and environmental exposures. The overall impact of these

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social communication and the presence of restricted interests and repetitive behaviors. Although behavioral interventions are numerous, there are no Federal Drug Administration approved pharmacological treatments for the core symptoms of ASD. The neuropeptide oxytocin has been studied in animals for decades

A reliable diagnosis of autism spectrum disorder (ASD) is difficult to make until after toddlerhood. Detection in an earlier age enables early intervention, which is typically more effective. Recent studies of the development of brain and behavior in infants and toddlers have provided important insights in the diagnosis of autism. This extensive review focuses on published studies of predicting the

Various genetic and environmental factors have been suggested to cause autism spectrum disorders (ASDs). A variety of animal models of ASDs have been developed and used to investigate the mechanisms underlying the pathogenesis of ASDs. These animal models have contributed to clarifying that abnormalities in neuronal morphology and neurotransmission are responsible for the onset of ASDs. In recent years

Neuroglia are a large class of neural cells of ectodermal (astroglia, oligodendroglia, and peripheral glial cells) and mesodermal (microglia) origin. Neuroglial cells provide homeostatic support, protection, and defense to the nervous tissue. Pathological potential of neuroglia has been acknowledged since their discovery. Research of the recent decade has shown the key role of all classes of glial

The posterior cingulate cortex (PCC) plays pivotal roles in cognitive, social and emotional processing, as well as early neural development that supports complex interactions among different neural networks. Alterations in its local and long-range connectivity during resting state are often implicated in neuropathology of neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is characterized

In the past decades, the fields of microbiology and immunology have largely advanced by using germ-free animals and next-generation sequencing. Many studies revealed the relationship among gut microbiota, activation of immune system, and various diseases. Especially, some gut commensals can generate their antigen-specific T cells. It is becoming clear that commensal bacteria have important roles in

Cancer treatment has been evolving in recent decades from surgery, conventional chemotherapy and radiation therapy to targeted therapies and more recently immunotherapies. Despite significant improvement in the efficacy of treatment with the discovery of novel therapies targeting particular cancer-related gene and proteins and more recently the immune system-modulating biologics, still only patients

Type 1 diabetes (T1D) is an autoimmune disease caused by complex interactions between host genetics and environmental factors, culminating in the T-cell mediated destruction of the insulin producing cells in the pancreas. The rapid increase in disease frequency over the past 50 years or more has been too rapid to attribute to genetics. Dysbiosis of the gut microbiota is currently being widely investigated

Although there is associative evidence linking fecal microbiome profile to health and disease, many studies have not considered the confounding effects of dietary intake. Consuming food provides fermentable substrate which sustains the microbial ecosystem that resides with most abundance in the colon. Western, Mediterranean and vegetarian dietary patterns have a role in modulating the gut microbiota

Many components of the gastric non-Helicobacter pylori microbiota have been identified recently thanks to advances in DNA sequencing techniques. Several lines of evidence support the hypothesis that the gastric microbiome is essential for gastric disorders such as gastric cancer. Microbial interactions impact the pathophysiology of various gastric disorders. This chapter provides an overview of recent

Motor neuron diseases (MNDs) are a wide group of neurodegenerative disorders characterized by the degeneration of a specific neuronal type located in the central nervous system, the motor neuron (MN). There are two main types of MNs, spinal and cortical MNs and depending on the type of MND, one or both types are affected. Cortical MNs innervate spinal MNs and these control a variety of cellular targets

The influence of the microbiota on viral infection susceptibility and disease outcome is undisputable although varies among viruses. The purpose of understanding the interactions between microbiota, virus, and host is to identify practical, effective, and safe approaches that target microbiota for the prevention and treatment of viral diseases in humans and animals, as currently there are few effective

Gut bacteria are predominant microorganisms in the gut microbiota and have been recognized to mediate a variety of biotransformations of xenobiotic compounds in the gut. This review is focused on one of the gut bacterial xenobiotic metabolisms, reduction. Xenobiotics undergo different types of reductive metabolisms depending on chemically distinct groups: azo (-NN-), nitro (-NO2), alkene (-CC-), ketone

The gut microbiota (GM) composition varies among individuals and is influenced by intrinsic (genetics, age) and extrinsic (environment, diet, lifestyle) factors. An imbalance or dysbiosis is directly associated with the development of several illnesses, due to the potential increase in intestinal permeability leading to a systemic inflammation triggered by higher levels of circulating lipopolysaccharides

Autophagy is a highly conserved lysosomal degradation pathway responsible for rapid elimination of unwanted cytoplasmic materials in response to stressful conditions. This cytoprotective function is essential for maintenance of cellular homeostasis and is mediated by conserved autophagy-related genes (ATG) and autophagic receptors. Impairment of autophagy frequently results in a wide variety of human

We provide a brief overview of the topological features found in structured proteins and of the dynamical processes that involve knots. We then discuss the knotted states that arise in the intrinsically disordered polyglutamine and α-synuclein. We argue that the existence of the knotted conformations stalls degradation by proteases and thus enhances aggregation. This mechanism works if the length of

Growing evidence suggests that imbalances in resident microbes (dysbiosis) can promote chronic inflammation, immune-subversion, and production of carcinogenic metabolites, thus leading to neoplasia. Yet, evidence to support a direct link of individual bacteria species to human sporadic cancer is still limited. This chapter focuses on several emerging bacterial toxins that have recently been characterized

Autophagy is a highly conserved degradation process that clears damaged intracellular macromolecules and organelles in order to maintain cellular health. Dysfunctional autophagy is fundamentally linked to the development of various human disorders and pathologies. The use of the nematode Caenorhabditis elegans as a model system to study autophagy has improved our understanding of its regulation and

Intrinsically disordered proteins (IDPs) possess the property of inherent flexibility and can be distinguished from other proteins in terms of lack of any fixed structure. Such dynamic behavior of IDPs earned the name “Dancing Proteins.” The exploration of these dancing proteins in viruses has just started and crucial details such as correlation of rapid evolution, high rate of mutation and accumulation

Autophagy is a major catabolic pathway that must be tightly regulated to maintain cellular homeostasis. Protein intrinsic disorder provides a very suitable conformation for regulation; accordingly, the molecular machinery of autophagy is significantly enriched in intrinsically disordered proteins and protein regions (IDPs/IDPRs). Despite experimental challenges that the characterization of IDPRs encounters

Mitochondria are highly dynamics organelles that provide the necessary energy for cellular functions. However, when they are dysfunctional, they can, by contrast, be very harmful for the cell. Mitophagy ensures their recycling and preserves cell performance. This mechanism is particularly important in neurons because they use a lot of energy. Failed mitophagy can thus affect the development of neurons

The molecular machinery of macroautophagy consists of Atg proteins and supports cytoplasmic constituent degradation in lysosomes as its canonical function, phagosome maturation and exocytosis. These different biological processes contribute to cell intrinsic, innate and adaptive immunity. For the respective immune responses, Atg proteins mediate direct pathogen degradation, inflammation restriction

The development of chronic lung disease occurs as a consequence of multiple cellular events that involve an initial insult which often leads to the development of chronic inflammation, and the dysregulation of cellular proliferation and cell death mechanisms. Multiple cell types in the lung are key to the respiratory and protective/barrier functions necessary to manage the chronic exposures to environmental

Autophagy is a crucial cellular degradation and recycling pathway. During autophagy double-membrane vesicles, called autophagosomes, encapsulate cellular components and deliver their cargo to the lytic compartment for degradation. Formation of autophagosomes is regulated by the Atg1 kinase complex in yeast and the homologous ULK1 kinase complex in mammals. While research on Atg1 and ULK1 has advanced

During the last decades, the potential harmfulness derived from the exposure to environmental pollutants has been largely demonstrated, with associated damages ranging from geno- and cyto-toxicity to tissue malfunction and alterations in organism physiology. Autophagy is an evolutionarily-conserved cellular mechanism essential for cellular homeostasis, which contributes to protect cells from a wide

Autophagic-lysosomal degradation is essential for the maintenance of normal homeostasis in eukaryotic cells. Several types of such self-degradative and recycling pathways have been identified. From these, probably the least known autophagic process is crinophagy, during which unnecessary or obsolete secretory granules directly fuse with late endosomes/lysosomes as a means of rapid elimination of unused

The interactions between proteins and membranes play critical roles in signal transduction, cell motility, and transport, and they are involved in many types of diseases. Molecular dynamics (MD) simulations have greatly contributed to our understanding of protein–membrane interactions, promoted by a dramatic development of MD-related software, increasingly accurate force fields, and available computer

In this chapter the scale-consistent approach to the derivation of coarse-grained force fields developed in our laboratory is presented, in which the effective energy function originates from the potential of mean force of the system under consideration and embeds atomistically detailed interactions in the resulting energy terms through use of Kubo's cluster-cumulant expansion, appropriate selection