Beta-Glucan in Foods and Health Benefits

Many articles and manuscripts focusing on the structure, function, mechanism of action, and effects of β-glucan have been published recently [...]

Golgi staining of neurons: Oxidation-state dependent spread of chemical reaction identifies a testable property of the connectome

Camillo Golgi observed reticular nature of the nervous system by his staining method. Ramon Cajal modified this protocol to obtain staining restricted to individual neurons, in support of the cell theory. Close examination shows that Golgi used an oxidizing agent to pre-treat the brain tissue before the staining reaction and Cajal used an additional oxidizing agent for the same step. It shows that oxidation state of the tissue has a crucial role in determining the spread of Golgi chemical reaction between neurons. The correct structure-function mechanism of brain functions may reveal the nature of the route through which the staining reaction spreads between neurons under decreasing oxidation states. Present work examines the chemical reaction behind the staining, explores the role of oxidizing agents in limiting the stain to individual neurons, and discusses a probable property of the connectome that can provide a gateway for an oxidation state-dependent spread of staining reaction.

The molecular pathogenesis of repeat expansion diseases

Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.

Mass Spectrometry for O-GlcNAcylation

O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) at proteins with low-abundance expression level and species diversity, shows important roles in plenty of biological processes. O-GlcNAcylations with abnormal expression levels are associated with many diseases. Systematically profiling of O-GlcNAcylation at qualitative or quantitative level is vital for their function understanding. Recently, the combination of affinity enrichment, metabolic labeling or chemical tagging with mass spectrometry (MS) have made significant contributions to structure-function mechanism elucidating of O-GlcNAcylations in organisms. Herein, this review provides a comprehensive update of MS-based methodologies for quali-quantitative characterization of O-GlcNAcylation.

Small molecule splicing modifiers with systemic HTT-lowering activity

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels.

On Penrose’s theory of objective gravitationally induced wave function reduction

In this paper, the formal structure of Penrose’s gravitationally induced reduction of the wave function mechanism is analyzed. It is shown that pushing Penrose’s argument forward leads to the interpretation of quantum coherence in microscopic systems as an observable signature violation of general covariance. We discuss potential avenues to avoid this conclusion, among them emergent quantum mechanics and super-determinism.

To Leverage the Innovation Capability by Co-creation of Human-Machine

Although a societal consensus has been reached about the partnership between human beings and smart machines, limited research has been carried out to consider advances in its combination pattern, function mechanism, and developing creativity. Based on occurred disruptive changes form theory to practice, a new paradigm of co-creation by synergistic human-machine is proposed, which refers to that interaction of human-machine learning in a holistic system increase complementarity of abilities and integration of wisdom to realize an augmented synergy made up of hybrid intelligences. This augmented intelligence can effectively account for shifts in business logic and the productive solutions to the multiple complex problems during smart manufacturing. It has been discovered that the positive consequences of synergistic human-machine co-creation include not only sustainable labor patterns, but the ability to overcome multiple complexities and steadily increase business value. All this is further elaborated in the Baizhentang Foods case. This paper discusses the main prospects of the theoretical developments presented here for future research on organizational behavior and a synergistic human-machine structure.

NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson’s disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.

Evidence for an FMR1 mRNA Gain-Of-Function Toxicity Mechanism in the Pathogenesis of Fragile-X Associated Premature Ovarian Insufficiency

Fragile X-associated premature ovarian insufficiency (FXPOI) is caused by expansion of a CGG repeat sequence located in the 5’ untranslated region of the FMR1 gene. Women with FXPOI have a depleted ovarian reserve, resulting in amenorrhea, hypoestrogenism, and loss of fertility before the age of 40. FXPOI is caused by CGG sequence expansions to lengths between 55 and 200 repeats, known as a FMRI premutation, however the mechanism by which the premutation drives disease pathogenesis remains unclear. Two main hypotheses exist, which describe an mRNA toxic gain-of-function mechanism or that repeat-associated non-AUG (RAN) translation results in the production of an abnormal protein, called FMRpolyG. We have developed an in vitro granulosa cell model of the FMR1 premutation by ectopically expressing CGG-repeat RNA and FMRpolyG protein. We show that expanded CGG-repeat RNA accumulated in intranuclear RNA structures, and these aggregates were able to cause significant granulosa cell death independent of FMRpolyG expression. Furthermore, using an innovative RNA pulldown, mass spectrometry-based approach we have identified proteins that bind CGG-repeat RNA in granulosa cells in vitro, and thus may be deregulated as consequence of this interaction. Collectively, these data provide evidence for the contribution of an mRNA gain-of-function mechanism to FXPOI disease biology.