Separable Roles for Neur and Ubiquitin in Delta Signalling in the CNS Lineages.

The execution of a Notch signal at the plasma membrane relies on the mechanical force exerted onto Notch by its ligand. It has been appreciated that the DSL ligands need to collaborate with a ubiquitin (Ub) ligase, either Neuralized or Mindbomb1, in order to exert this pulling force, but the role of ubiquitylation per se is uncertain. Regarding the Delta-Neur pair, it is documented that neither the Neur catalytic domain nor the Delta intracellular lysines (putative Ub acceptors) are needed for activity.

The meaning of ubiquitylation of the DSL ligand Delta for the development of Drosophila.

Background: Ubiquitylation (ubi) of the intracellular domain of the Notch ligand Delta (Dl) by the E3 ligases Neuralized (Neur) and Mindbomb1 (Mib1) on lysines (Ks) is thought to be essential for the its signalling activity. Nevertheless, we have previously shown that DlK2R-HA, a Dl variant where all Ks in its intracellular domain (ICD) are replaced by the structurally similar arginine (R), still possess weak activity if over-expressed. This suggests that ubi is not absolutely required for Dl signalling.

Using to Analyse the Human Paralogs of the ESCRT-III Core Component Shrub/CHMP4/Snf7 and Its Interactions with Members of the LGD/CC2D1 Family.

The evolutionary conserved ESCRT-III complex is a device for membrane remodelling in various cellular processes, such as the formation of intraluminal vesicles (ILVs), cytokinesis, and membrane repair. The common theme of all these processes is the abscission of membrane away from the cytosol. At its heart in is Shrub, CHMP4 in humans, which dynamically polymerises into filaments through electrostatic interactions among the protomers.

Increasing the Batch Size of a QESD Crystallization by Using a MSMPR Crystallizer.

Quasi-emulsion solvent diffusion (QESD) crystallizations can improve the micromeritic properties of drugs and excipients. A solution is dispersed in a miscible antisolvent as a transient emulsion. Using this technique, substances that normally crystallize in the form of e.

Towards a better understanding of the role of stabilizers in QESD crystallizations.

Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles.

100% visual inspection of tablets produced with continuous direct compression and coating.

Visual appearance of tablets is an important property for patients. Since the visual appearance is most strongly influenced by the applied coating, this necessitates a high level of process control and homogeneity in the coating process. In recent years, a number of tablet coaters have been developed that can be used in combination with continuous tablet production lines.

Enabling the direct compression of metformin hydrochloride through QESD crystallization.

Metformin hydrochloride is a drug used in the treatment of type 2 diabetes. It shows very poor flowability and agglomeration under storage so that a direct compression of the material into tablets has not yet been successfully realized. In a previous study the authors showed that a quasi-emulsion solvent-diffusion (QESD) crystallization technique can be used to drastically improve the flowability and reduce storage agglomeration of this drug.

The role of ligand endocytosis in notch signalling.

The Notch signalling receptor is a mechanoreceptor that is activated by force. This force elicits a conformational change in Notch that results in the release of its intracellular domain into the cytosol by two consecutive proteolytic cleavages. In most cases, the force is generated by pulling of the ligands on the receptor upon their endocytosis.

Improving flowability and reducing storage agglomeration of metformin hydrochloride through QESD crystallization.

Metformin hydrochloride is a drug used in the treatment of type 2 diabetes and is administered orally using high-dose tablets. Due to its poor flowability and agglomeration during storage, metformin is commonly processed using an intermediate step such as granulation before the material can be compressed into tablets. Spherical crystallization is a method, which can be used to improve the flowability and tabletability of drugs and excipients.

Lethal (2) giant discs (Lgd)/CC2D1 is required for the full activity of the ESCRT machinery.

Background: A major task of the endosomal sorting complex required for transport (ESCRT) machinery is the pinching off of cargo-loaded intraluminal vesicles (ILVs) into the lumen of maturing endosomes (MEs), which is essential for the complete degradation of transmembrane proteins in the lysosome. The ESCRT machinery is also required for the termination of signalling through activated signalling receptors, as it separates their intracellular domains from the cytosol. At the heart of the machinery lies the ESCRT-III complex, which is required for an increasing number of processes where membrane regions are abscised away from the cytosol.

Unravelling of Hidden Secrets: The Tumour Suppressor Lethal (2) Giant Discs (Lgd)/CC2D1, Notch Signalling and Cancer.

The endosomal pathway plays a pivotal role upon signal transduction in the Notch pathway. Recent work on lethal (2) giant discs (lgd) points to an additional critical role in avoiding uncontrolled ligand-independent signalling during trafficking of the Notch receptor through the endosomal pathway to the lysosome for degradation. In this chapter, we will outline the journey of Notch through the endosomal system and present an overview of the current knowledge about Lgd and its mammalian orthologs Lgd1/CC2D1b and Lgd2/CC2D1a.

Multiple sclerosis and COVID-19.

This paper reviews currently available data on the novel coronavirus and clinical features of COVID-19, followed by a detailed section on possible modifications of immunomodulatory therapy in multiple sclerosis patients with COVID-19, based on what we know so far. There are discussed: (i) The COVID-19 disease (Epidemiological background SARS-CoV-1 coronavirus; Autoimmune response to COVID-19; Asymptomatic course; SARS-CoV-2 test; COVID-19 symptoms), (ii) Treatment of COVID-19 (Experimental plasma treatment; Antiviral therapy; Antimalarial treatment scheme; Biological treatment; Corticosteroid treatment; Symptomatic treatment; Vaccine preparation) and (iii) Multiple sclerosis and SARS-CoV-2 infection (Epidemiological recommendation).

Alexithymic and autistic traits: Relevance for comorbid depression and social phobia in adults with and without autism spectrum disorder.

Adults with autism often develop mental health problems such as depression and social phobia. The reasons for this are still unclear. Many studies found that alexithymia plays an important role in mental health problems like depression.

BrainSpace: a toolbox for the analysis of macroscale gradients in neuroimaging and connectomics datasets.

Understanding how cognitive functions emerge from brain structure depends on quantifying how discrete regions are integrated within the broader cortical landscape. Recent work established that macroscale brain organization and function can be described in a compact manner with multivariate machine learning approaches that identify manifolds often described as cortical gradients. By quantifying topographic principles of macroscale organization, cortical gradients lend an analytical framework to study structural and functional brain organization across species, throughout development and aging, and its perturbations in disease.

Expanding crystallization tools for nucleic acid complexes using U1A protein variants.

The major bottlenecks in structure elucidation of nucleic acids are crystallization and phasing. Co-crystallization with proteins is a straight forward approach to overcome these challenges. The human RNA-binding protein U1A has previously been established as crystallization module, however, the absence of UV-active residues and the predetermined architecture in the asymmetric unit constitute clear limitations of the U1A system.

Thermodynamics of amyloid fibril formation from chemical depolymerization.

Amyloid fibrils are homo-molecular protein polymers that play an important role in disease and biological function. While much is known about their kinetics and mechanisms of formation, the origin and magnitude of their thermodynamic stability has received significantly less attention. This is despite the fact that the thermodynamic stability of amyloid fibrils is an important determinant of their lifetimes and processing in vivo.

Nitrogenase Inhibition Limited Oxygenation of Earth's Proterozoic Atmosphere.

Cyanobacteria produced the oxygen that began to accumulate on Earth 2.5 billion years ago, at the dawn of the Proterozoic Eon. By 2.

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Archaeal Histone Contributions to the Origin of Eukaryotes.

The eukaryotic lineage arose from bacterial and archaeal cells that underwent a symbiotic merger. At the origin of the eukaryote lineage, the bacterial partner contributed genes, metabolic energy, and the building blocks of the endomembrane system. What did the archaeal partner donate that made the eukaryotic experiment a success? The archaeal partner provided the potential for complex information processing.

Discovery of potent polyphosphate kinase 1 (PPK1) inhibitors using structure-based exploration of PPK1Pharmacophoric space coupled with docking analyses.

Inorganic polyphosphate (polyP) is present in all living forms of life. Studied mainly in prokaryotes, polyP and its associated enzymes are vital in diverse metabolic activities, in some structural functions, and most importantly in stress responses. Bacterial species, including many pathogens, encode a homolog of a major polyP synthesis enzyme, Poly Phosphate Kinase (PPK) with 2 different genes coding for PPK1 and PPK2.

Ubiquitylation-independent activation of Notch signalling by Delta.

Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling.

A Comparison of 2- and 3-dimensional Healing Assessment after Endodontic Surgery Using Cone-beam Computed Tomographic Volumes or Periapical Radiographs.

Introduction: The aim of this study was to compare the assessment of healing after endodontic microsurgery using 2-dimensional (2D) periapical films versus 3-dimensional (3D) cone-beam computed tomographic (CBCT) imaging.

Methods: The healing of 51 teeth from 44 patients was evaluated using Molven's criteria (2D) and modified PENN 3D criteria. The absolute area (2D) and volume (3D) changes of apical lesions preoperatively and at follow-up were calculated by segmentation using OsiriX software (Pixmeo, Bernex, Switzerland) and ITK-Snap (free software).

Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological Diseases.

D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse.

Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses.

High expression of Nek2 has been detected in several types of cancer and it represents a novel target for human cancer. In the current study, structure-based pharmacophore modeling combined with multiple linear regression (MLR)-based QSAR analyses was applied to disclose the structural requirements for NEK2 inhibition. Generated pharmacophoric models were initially validated with receiver operating characteristic (ROC) curve, and optimum models were subsequently implemented in QSAR modeling with other physiochemical descriptors.