Generation of mAb Variants with Less Attractive Self-Interaction but Preserved Target Binding by Well-Directed Mutation.

Strongly attractive self-interaction of therapeutic protein candidates can impose challenges for manufacturing, filling, stability, and administration due to elevated viscosity or aggregation propensity. Suitable formulations can mitigate these issues to a certain extent. Understanding the self-interaction mechanism on a molecular basis and rational protein engineering provides a more fundamental approach, and it can save costs and efforts as well as alleviate risks at later stages of development.

Epigenetic regulation of neural lineage elaboration: Implications for therapeutic reprogramming.

The vulnerability of the mammalian brain is mainly due to its limited ability to generate new neurons once fully matured. Direct conversion of non-neuronal cells to neurons opens up a new avenue for therapeutic intervention and has made great strides also for in vivo applications in the injured brain. These great achievements raise the issue of adequate identity and chromatin hallmarks of the induced neurons.

When and why telepressure and technostress creators impair employee well-being.

. This article describes the effects of two specific information and communication technology (ICT) demands (telepressure, technostress creators) on employee well-being, and investigates a mediating effect of detachment (Study 1) and moderating effects of technostress inhibitors on the effects of ICT demands on well-being (Study 2) and detachment (Study 3). .

Implementation of robotic devices in nursing care. Barriers and facilitators: an integrative review.

Background: Robots in healthcare are gaining increasing attention; however, their implementation is challenging due to the complexity of both interventions themselves and the contexts in which they are implemented. The objective of this integrative review is to identify barriers to and facilitators of the implementation of robotic systems in nursing.

Methods: Articles published from 2002 to 2019 reporting on projects to implement robotic devices in nursing care were searched on Medline (via PubMed), CINAHL and databases on funded research projects (Community Research and Development Information Services and Technische Informationsbibliothek) and in journals for robotic research in November 2017 and July 2019 for an update.

Azo-dimethylaminopyridine-functionalized Ni(II)-porphyrin as a photoswitchable nucleophilic catalyst.

We present the synthesis and the photochemical and catalytic switching properties of an azopyridine as a photoswitchable ligand, covalently attached to a Ni(II)-porphyrin. Upon irradiation with 530 nm (green light), the azopyridine switches to the configuration and coordinates with the Ni ion. Light of 435 nm (violet) isomerizes the ligand back to the configuration, which decoordinates for steric reasons.

Neuronal Reprogramming for Brain Repair: Challenges and Perspectives.

Brain injuries and neurodegenerative diseases elicit neuronal loss that persists because the adult mammalian brain lacks robust regenerative abilities. Direct reprogramming of local glial cells into neurons is a promising strategy for neuronal replacement in vivo. We discuss recent advances and future challenges in this approach to brain repair.

Framing biophysical and societal implications of multiple stressor effects on river networks.

Urbanization, agriculture, and the manipulation of the hydrological cycle are the main drivers of multiple stressors affecting river ecosystems across the world. Physical, chemical, and biological stressors follow characteristic patterns of occurrence, intensity, and frequency, linked to human pressure and socio-economic settings. The societal perception of stressor effects changes when moving from broad geographic regions to narrower basin or waterbody scales, as political and ecologically based perspectives change across scales.

Analysis of antibody self-interaction by bio-layer interferometry as tool to support lead candidate selection during preformulation and developability assessments.

Developability assessment of therapeutic mAb candidates before entering CMC development mitigates the risk of later failure because of manufacturing and stability issues. For mAbs derived from library based screenings, such evaluation starts with the first panning and ends with the selection of a lead candidate. This candidate should show, amongst others, high affine target binding and beneficial conformational as well as chemical stability.

A Missense Variant in Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions.

Cryoconcentration and 3D Temperature Profiles During Freezing of mAb Solutions in Large-Scale PET Bottles and a Novel Scale-Down Device.

Purpose: Small-scale models that simulate large-scale freezing of bulk drug substance of biopharmaceuticals are highly needed to define freezing and formulation parameters based on process understanding. We evaluated a novel scale-down device (SDD), which is based on a specially designed insulation cover, with respect to changes in concentration after freezing, referred to as cryoconcentration, and 3D temperature profiles. Furthermore, the effect of the initial monoclonal antibody (mAb) concentration on cryoconcentration was addressed.

Heterogeneity of astrocytes: Electrophysiological properties of juxtavascular astrocytes before and after brain injury.

Astrocyte heterogeneity is increasingly recognized, but still little is known about juxtavascular astrocytes with their somata directly adjacent to blood vessels, despite their importance after brain injury. As juxtavascular astrocytes originate from common progenitor cells, that is, have a clonal origin, they may intrinsically differ from other, non-juxtavascular astrocytes. To explore this, we examined the electrophysiological properties of these groups of astrocytes and the underlying ion channels.

The immunomodulatory role of Regnase family RNA-binding proteins.

RNA-binding proteins regulate RNA fate and govern post-transcriptional gene regulation. A new family of RNA-binding proteins is represented by regulatory RNases (Regnase, also known as Zc3h12 or MCPIP), which have emerged as important players in immune homoeostasis. Four members, Regnase1-4, have been identified to date.

Biophysical Characterization of Binary Therapeutic Monoclonal Antibody Mixtures.

Coformulations containing two therapeutic monoclonal antibodies (mAbs) could offer various benefits like enhanced therapeutic efficacy and better patient compliance. However, there are very few published studies on coformulations and binary mixtures of mAbs. It remains unclear to what extent mAbs with different physicochemical properties can be combined in solution without detrimental effects on protein stability.

Trnp1 organizes diverse nuclear membrane-less compartments in neural stem cells.

TMF1-regulated nuclear protein 1 (Trnp1) has been shown to exert potent roles in neural development affecting neural stem cell self-renewal and brain folding, but its molecular function in the nucleus is still unknown. Here, we show that Trnp1 is a low complexity protein with the capacity to phase separate. Trnp1 interacts with factors located in several nuclear membrane-less organelles, the nucleolus, nuclear speckles, and condensed chromatin.

The Effect of Point Mutations on the Biophysical Properties of an Antimicrobial Peptide: Development of a Screening Protocol for Peptide Stability Screening.

Therapeutic peptides and proteins show enormous potential in the pharmaceutical market, but high costs in discovery and development are limiting factors so far. Single or multiple point mutations are commonly introduced in protein drugs to increase their binding affinity or selectivity. They can also induce adverse properties, which might be overlooked in a functional screen, such as a decreased colloidal or thermal stability, leading to problems in later stages of the development.

Detection of feline coronavirus RNA, spike gene mutations, and feline coronavirus antigen in macrophages in aqueous humor of cats in the diagnosis of feline infectious peritonitis.

Uveitis is common in cats, and is often a feature of feline infectious peritonitis (FIP). We evaluated 3 tools for detection of feline coronavirus (FCoV) in aqueous humor: 1) a gene reverse-transcription real-time PCR (-RT-rtPCR) assay to detect FCoV RNA, 2) a spike gene mutation RT-rtPCR (-RT-rtPCR) assay to detect 2 point mutations in the spike gene of FCoV in cats positive by -RT-rtPCR, and 3) immunocytochemistry (ICC) for detection of FCoV antigen in aqueous humor macrophages. We studied 58 cats, including 31 cats with FIP and 27 control cats.

Crop nitrogen monitoring: Recent progress and principal developments in the context of imaging spectroscopy missions.

Nitrogen (N) is considered as one of the most important plant macronutrients and proper management of N therefore is a pre-requisite for modern agriculture. Continuous satellite-based monitoring of this key plant trait would help to understand individual crop N use efficiency and thus would enable site-specific N management. Since hyperspectral imaging sensors could provide detailed measurements of spectral signatures corresponding to the optical activity of chemical constituents, they have a theoretical advantage over multi-spectral sensing for the detection of crop N.

Biomedical Research Goes Viral: Dangers and Opportunities.

Researchers around the globe have been mounting, accelerating, and redeploying efforts across disciplines and organizations to tackle the SARS-CoV-2 outbreak. However, humankind continues to be afflicted by numerous other devastating diseases in increasing numbers. Here, we outline considerations and opportunities toward striking a good balance between maintaining and redefining research priorities.

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.

Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients.

Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy.

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.

Protein-Polydimethylsiloxane Particles in Liquid Vial Monoclonal Antibody Formulations Containing Poloxamer 188.

Surfactants play an important role in stabilizing proteins in liquid formulations against aggregate/particle formation during processing, handling, storage, and transportation. Only 3 surfactants are currently used in marketed therapeutic protein formulations: polysorbate 20, polysorbate 80, and poloxamer 188. While polysorbates are the most widely used surfactants, their intrinsic oxidative and hydrolytic degradation issues highlights the importance of alternative surfactants such as poloxamer 188.

Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regulators of Adult Neurogenesis.

The mammalian brain contains few niches for neural stem cells (NSCs) capable of generating new neurons, whereas other regions are primarily gliogenic. Here we leverage the spatial separation of the sub-ependymal zone NSC niche and the olfactory bulb, the region to which newly generated neurons from the sub-ependymal zone migrate and integrate, and present a comprehensive proteomic characterization of these regions in comparison to the cerebral cortex, which is not conducive to neurogenesis and integration of new neurons. We find differing compositions of regulatory extracellular matrix (ECM) components in the neurogenic niche.