Comparative activity of dimethyl fumarate derivative IDMF in three models relevant to multiple sclerosis and psoriasis.

Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory medication used to treat multiple sclerosis (MS) and psoriasis. Its skin sensitization property precludes its topical use, which is unfortunate for the treatment of psoriasis. Isosorbide di-(methyl fumarate) (IDMF), a novel derivative of DMF, was synthesized to circumvent this adverse reaction and unlock the potential of topical delivery, which could be useful for treating psoriasis in the subpopulation of psoriatic MS patients, as well as in the general population.

Episodic and associative memory from spatial scaffolds in the hippocampus.

Hippocampal circuits in the brain enable two distinct cognitive functions: the construction of spatial maps for navigation, and the storage of sequential episodic memories. Although there have been advances in modelling spatial representations in the hippocampus, we lack good models of its role in episodic memory. Here we present a neocortical-entorhinal-hippocampal network model that implements a high-capacity general associative memory, spatial memory and episodic memory.

Mepolizumab real-world effectiveness in severe asthma with an eosinophilic phenotype and overlapping severe allergic asthma.

Background: Some patients with severe asthma have overlapping allergic and eosinophilic phenotypes and may be eligible for anti-eosinophilic or anti-IgE biologics.

Objective: This post hoc sub-analysis assessed real-world mepolizumab effectiveness in patients with overlapping allergic and eosinophilic phenotypes, using 1-year data from the international, prospective REALITI-A study.

Methods: The clinically significant asthma exacerbation (CSE) rate was assessed 1 year prior to (pre-treatment) and following (follow-up) mepolizumab treatment, stratified by baseline total IgE levels (tIgE; <60, 60-<190, 190-<550, and ≥550 kU/L), atopic status (yes/no/unknown), prior omalizumab use (yes/no), geographic baseline omalizumab eligibility (eligible/non-eligible), and baseline tIgE level and blood eosinophil count (BEC) threshold combinations (<81 or ≥81 kU/L and <300 or ≥300 cells/µL).

Boronic Acid-Containing 3- pyrazolo[4,3-]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties.

The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues.

Discovery of novel pyrazoline insecticides.

Background: The pyrazoline insecticides, invented by Philips Duphar in the 1970s, provide excellent control of lepidopterans and coleopterans and introduced a novel mode of action (MoA) as sodium-channel-blocking insecticides, but were not commercialized due to unacceptable persistence. This MoA is less explored, with only two successfully commercialized insecticides derived from the pyrazoline class - the oxadiazine indoxacarb from FMC (developed by DuPont) and the semicarbazone metaflumizone, co-developed by BASF and Nihon Nohyaku.

Results: The design and synthesis of novel pyrazoline insecticides with improved biological efficacy and favorable environmental fate profile are described.