Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease.

Wnt signalling is an essential signalling system in neurogenesis, with a crucial role in synaptic plasticity and neuronal survival, processes that are disrupted in Alzheimer's disease (AD). Within this network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical Wnt-planar cell polarity (Wnt/PCP) pathway in AD remains to be determined.

Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases.

The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells.

WNT7A-positive dendritic cytonemes control synaptogenesis in cortical neurons.

Synaptogenesis involves the transformation of dendritic filopodial contacts into stable connections with the exact apposition of synaptic components. Signalling triggered by Wnt/β-catenin and calcium has been postulated to aid this process. However, it is unclear how such a signalling process orchestrates synapse formation to organise the spatial arrangement of synapses along dendrites.

In vitro and in vivo pharmacological characterization of dasotraline, a dual dopamine and norepinephrine transporter inhibitor in vivo.

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC =3 nM) and hNET (IC =4 nM relative to hSERT(IC =15 nM).

Air pollution perception in ten countries during the COVID-19 pandemic.

As largely documented in the literature, the stark restrictions enforced worldwide in 2020 to curb the COVID-19 pandemic also curtailed the production of air pollutants to some extent. This study investigates the perception of the air pollution as assessed by individuals located in ten countries: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the USA. The perceptions towards air quality were evaluated by employing an online survey administered in May 2020.

Impact of COVID-19 pandemic on mobility in ten countries and associated perceived risk for all transport modes.

The restrictive measures implemented in response to the COVID-19 pandemic have triggered sudden massive changes to travel behaviors of people all around the world. This study examines the individual mobility patterns for all transport modes (walk, bicycle, motorcycle, car driven alone, car driven in company, bus, subway, tram, train, airplane) before and during the restrictions adopted in ten countries on six continents: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. This cross-country study also aims at understanding the predictors of protective behaviors related to the transport sector and COVID-19.

A survey dataset to evaluate the changes in mobility and transportation due to COVID-19 travel restrictions in Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa, United States.

COVID-19 pandemic has heavily impacted the global community. To curb the viral transmission, travel restrictions have been enforced across the world. The dataset documents the mobility disruptions and the modal shifts that have occurred as a consequence of the restrictive measures implemented in ten countries: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States.

Survey data regarding perceived air quality in Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa, United States before and during Covid-19 restrictions.

The dataset deals with the air quality perceived by citizens before and during the enforcement of COVID-19 restrictions in ten countries around the world: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. An online survey conveniently translated into Chinese, English, Italian, Norwegian, Persian, Portuguese collected information regarding the perceived quality of air pollution according to a Likert scale. The questionnaire was distributed between 11-05-2020 and 31-05-2020 and 9 394 respondents took part.

High-Throughput Screening Strategy Identifies Allosteric, Covalent Human D-Amino Acid Oxidase Inhibitor.

Genome-wide association studies have linked polymorphisms in the gene G72 to schizophrenia risk in several human populations. Although controversial, biochemical experiments have suggested that the mechanistic link of G72 to schizophrenia is due to the G72 protein product, pLG72, exerting a regulatory effect on human D-amino acid oxidase (hDAAO) activity. In an effort to identify hDAAO inhibitors of novel mechanism of action, we designed a pLG72-directed hDAAO activity assay suitable for high-throughput screening (HTS).

Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open conformation.

The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders.

Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules.

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.

In vitro and in vivo evaluation of O-alkyl derivatives of tramadol.

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency.

F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affinity N-formylpeptide receptor.

F2L (formylpeptide receptor (FPR)-like (FPRL)-2 ligand), a highly conserved acetylated peptide derived from the amino-terminal cleavage of heme-binding protein, is a potent chemoattractant for human monocytes and dendritic cells, and inhibits LPS-induced human dendritic cell maturation. We recently reported that F2L is able to activate the human receptors FPRL-1 and FPRL2, two members of the FPR family, with highest selectivity and affinity for FPRL2. To facilitate delineation of mechanisms of F2L action in vivo, we have now attempted to define its mouse receptors.

Properly designed modular asymmetric synthesis for enantiopure sulfinamide auxiliaries from N-sulfonyl-1,2,3-oxathiazolidine-2-oxide agents.

Simple and practical asymmetric synthesis of functionally differentiated aminoindanol based endo-N-sulfonyl 1,2,3-oxathiazolidine-2-oxide as sulfinyl transfer agents are developed. The importance of these new and unique sulfinyl transfer reagents are exemplified by the expedient production of several sulfinamide ligands, including either enantiomer of (R)-tert-butanesulfinamide in excellent yields and enantiopurities.