Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Male Mice.

Background: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, posttraumatic stress disorder, dementia, and age-related cognitive decline. Although BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis, its significance as a pharmacological target has not been tested.

Methods: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis.

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice.

Background: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested.

Methods: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis.

A novel antibiotic class targeting the lipopolysaccharide transporter.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years.

Intensified acute in-hospital physiotherapy for patients after hip fracture surgery: a pragmatic, randomized, controlled feasibility trial.

Purpose: Intensified acute in-hospital physiotherapy (IP) after hip fracture (HF) may enhance patient's ability to regain basic mobility at discharge. The primary objective was to assess the feasibility of IP. Secondary to estimate the effect of IP on regained basic mobility at discharge.

Leveraging Cell Painting Images to Expand the Applicability Domain and Actively Improve Deep Learning Quantitative Structure-Activity Relationship Models.

The search for chemical hit material is a lengthy and increasingly expensive drug discovery process. To improve it, ligand-based quantitative structure-activity relationship models have been broadly applied to optimize primary and secondary compound properties. Although these models can be deployed as early as the stage of molecule design, they have a limited applicability domain─if the structures of interest differ substantially from the chemical space on which the model was trained, a reliable prediction will not be possible.

Machine learning-powered antibiotics phenotypic drug discovery.

Identification of novel antibiotics remains a major challenge for drug discovery. The present study explores use of phenotypic readouts beyond classical antibacterial growth inhibition adopting a combined multiparametric high content screening and genomic approach. Deployment of the semi-automated bacterial phenotypic fingerprint (BPF) profiling platform in conjunction with a machine learning-powered dataset analysis, effectively allowed us to narrow down, compare and predict compound mode of action (MoA).

mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.

Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells.

White-to-brown metabolic conversion of human adipocytes by JAK inhibition.

The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity.

A random motility assay based on image correlation spectroscopy.

We demonstrate the random motility (RAMOT) assay based on image correlation spectroscopy for the automated, label-free, high-throughput characterization of random cell migration. The approach is complementary to traditional migration assays, which determine only the collective net motility in a particular direction. The RAMOT assay is less demanding on image quality compared to single-cell tracking, does not require cell identification or trajectory reconstruction, and performs well on live-cell, time-lapse, phase contrast video microscopy of hundreds of cells in parallel.

Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man.

Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression of GLP1R is much lower in primates than in rodents, the described C-cell proliferative lesions may not be relevant to man.

Functional monoclonal antibody acts as a biased agonist by inducing internalization of metabotropic glutamate receptor 7.

Background And Purpose: The mGlu(7) receptors are strategically located at the site of vesicle fusion where they modulate the release of the main excitatory and inhibitory neurotransmitters. Consequently, they are implicated in the underlying pathophysiology of CNS diseases such as epilepsy and stress-related psychiatric disorders. Here, we characterized a selective, potent and functional anti-mGlu(7) monoclonal antibody, MAB1/28, that triggers receptor internalization.

Topological analysis of the complex formed between neurokinin A and the NK2 tachykinin receptor.

Neurokinin A stimulates physiological responses in the peripheral and central nervous systems upon interacting primarily with the tachykinin NK2 receptor (NK2R). In this study, the structure of NKA bound to the NK2R is characterised by use of fluorescence resonance energy transfer. Four fluorescent NKA analogues with Texas red introduced at amino acid positions 1, 4, 7 and 10 were prepared.

Identification of the extracellular loop 2 as the point of interaction between the N terminus of the chemokine MIP-1alpha and its CCR1 receptor.

Macrophage inflammatory peptide-1alpha (MIP-1alpha)/CC-chemokine receptor ligand 3 is an 8-kDa peptide that induces chemotaxis of various lymphocytes to sites of inflammation through interaction with the G protein-coupled chemokine receptors CCR1 and CCR5. We recently described the preparation of a photoactivatable derivative of MIP-1alpha labeled with a benzophenone group at the extreme N-terminal end, which is a determinant for the agonist character of chemokines. Benzophenone-MIP-1alpha is a full agonist that specifically and covalently labels CCR1 and CCR5 receptors upon irradiation.

The neurokinin A receptor activates calcium and cAMP responses through distinct conformational states.

G protein-coupled receptors are thought to mediate agonist-evoked signal transduction by interconverting between discrete conformational states endowed with different pharmacological and functional properties. In order to address the question of multiple receptor states, we monitored rapid kinetics of fluorescent neurokinin A (NKA) binding to tachykinin NK2 receptors, in parallel with intracellular calcium, using rapid mixing equipment connected to real time fluorescence detection. Cyclic AMP accumulation responses were also monitored.

Synthesis and characterization of fluorescent and photoactivatable MIP-1alpha ligands and interactions with chemokine receptors CCR1 and CCR5.

Photoaffinity and fluorescent analogues of the 70-amino acid chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) were designed, synthesized, characterized, and applied to probe MIP-1alpha interactions with the chemokine receptors CCR1 and CCR5. The photoactivatable MIP-1alpha ligand, BP-MIP-1alpha, and the fluorescent ligand, Flu-MIP-1alpha were prepared by selective chemical coupling of p-benzoylphenylthiocarbamyl or fluoresceinthiocarbamyl, respectively, at the N-terminus of MIP-1alpha. Both ligands BP-MIP-1alpha and Flu-MIP-1alpha retained high binding affinity and agonist potency at CCR1 and CCR5.

Steric hindrance mutagenesis versus alanine scan in mapping of ligand binding sites in the tachykinin NK1 receptor.

Residues in transmembrane domain (TM)-III, TM-V, TM-VI, and TM-VII believed to be facing the deep part of the presumed main ligand-binding pocket of the NK1 receptor were probed by alanine substitution and introduction of residues with larger and/or chemically distinct side chains. Unaltered or even improved binding affinity for four peptide agonists, substance P, substance P-O-methyl ester, eledoisin, and neurokinin A, as well as normal EC50 values for substance P in stimulating phosphatidylinositol turnover indicated that these mutations did not alter the overall functional integrity of the receptor. The alanine substitutions in general had only minor effects on nonpeptide antagonist binding.

Characterization of non-peptide antagonist and peptide agonist binding sites of the NK1 receptor with fluorescent ligands.

Ligand recognition of the NK1 receptor (substance P receptor) by peptide agonist and non-peptide antagonist has been investigated and compared by the use of fluorescent ligands and spectrofluorometric methods. Analogues of substance P (SP) labeled with the environment-sensitive fluorescent group 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) at either position 3, 8, or 11 or with fluorescein at the Nalpha position were synthesized and characterized. Peptides modified at the alpha-amino group or at positions 3 or 11 conserved a relatively good affinity for NK1 and agonistic properties.

Conserved HisVI-17 of the NK-1 receptor is involved in binding of non-peptide antagonists but not substance P.

Residue number 17 in transmembrane segment VI has been shown to be crucial for the binding of agonists in G-protein-coupled receptors for the monoamines. In many peptide receptors a histidyl residue has been conserved at this position. We find that replacement of HisVI-17 in the NK-1 receptor with either glutamine, phenylalanine, or alanine has no apparent effect on the binding of the natural peptide ligand substance P or on the agonist induced increase in inositolphosphate turnover.