Biology subjects

Maxwell, K.

Publications and source records attributed to Maxwell, K..

4 recordsLinked to original sources

bioRxiv2024

Distinct roles for MNK1 and MNK2 in social and cognitive behavior through kinase-specific regulation of the synaptic proteome and phosphoproteome

Local mRNA translation is required for adaptive changes in the synaptic proteome. The mitogen-activated protein kinase (MAPK) interacting protein kinases 1 and 2 (MNK1 and MNK2) have emerged as key regulators of neuronal translation, primarily through phosphorylation of the eukaryotic initiation factor 4E (eIF4E). The therapeutic benefits of targeting the MNKs are being investigated for nervous system conditions and disorders that affect translation, including autism, pain, and cancer. However, it is still unclear if MNK1 and MNK2 regulate distinct aspects of neuronal translation and how the activity of each kinase is associated with the synaptic and behavioral features linked to MNK signaling. To examine the individual neurobiological functions of each kinase, we used knockout mice lacking either MNK1 or MNK2. We found that the knockout of MNK1 and MNK2 leads to different social and cognitive behavioral profiles and distinct alterations of the cortical synaptic proteome, transcriptome, and phosphoproteome. Loss of MNK1 was associated with an increase in ribosomal protein expression, whereas deletion of MNK2 decreased the expression and phosphorylation of synaptic proteins. Together, our findings provide evidence for a high degree of functional specialization of the MNKs in synaptic compartments and suggest that pharmacological inhibition of individual MNK may provide more specific targets for neurological disorders.

neuroscience↗

bioRxiv2022

The durability of long-lasting insecticidal nets treated with and without piperonyl butoxide (PBO) in Uganda.

Long Lasting Insecticidal Nets (LLINs) supplemented with the synergist piperonyl butoxide have been developed in response to growing pyrethroid resistance however their durability in the field remains poorly described. A pragmatic cluster-randomised trial was embedded into Ugandas 2017-2018 distribution to compare the durability of LLINs with and without PBO A total of 104 clusters were included with each receiving one of four LLIN products, two with pyrethroid+PBO (Olyset Plus and PermaNet 3.0) and two pyrethroid-only (Olyset Net and PermaNet 2.0). Nets were sampled at baseline, 12, and 25 months post-distribution to assess physical condition, chemical content, and bioefficacy. Physical condition was quantified using proportionate Hole Index and chemical content measured using high-performance liquid chromatography. Bioefficacy was assessed with three-minute WHO Cone and Wireball assays using pyrethroid-resistant An. gambiae, with 1hr knockdown and 24hr mortality recorded. There was no difference in physical durability between LLIN products assessed (p=0.644). The pyrethroid content of all products remained relatively stable across timepoints but PBO content declined by 55% (p<0.001) and 58% (p<0.001) for Olyset Plus and PermaNet 3.0 respectively. Both PBO LLINs were highly effective against pyrethroid-resistant mosquitoes when new, knocking down all mosquitoes. However, bioefficacy declined over time with Olyset Plus knocking down 45.72% (95% CI: 22.84-68.62, p=0.021) and Permanet 3.0 knocking down 78.57% (95% CI: 63.57-93.58, p<0.001) after 25 months. Here we demonstrate that both Olyset Plus and PermaNet 3.0 are as durable as their pyrethroid-only equivalents and had superior bioefficacy against pyrethroid-resistant An. gambiae. However, the superiority of PBO-LLINs decreased with operational use, correlating with a reduction in total PBO content. This decline in bioefficacy after just two years is concerning and there is an urgent need to assess the durability of PBO LLINs in other settings.

zoology↗

bioRxiv2021

Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. One sentence summaryDevelopment of personalized therapy for Wolfram syndrome using genetics and iPSC model.

genetics↗

bioRxiv2018

Heterogeneous exposure and hotspots for malaria vectors at three study sites in Uganda

Heterogeneity in malaria transmission has household, temporal, and spatial components. These factors are relevant for improving the efficiency of malaria control by targeting heterogeneity. To quantify variation, we analyzed mosquito counts from entomological surveillance conducted at three study sites in Uganda that varied in malaria transmission intensity. Using a Bayesian zero-inflated negative binomial model, validated via a comprehensive simulation study, we quantified household differences in malaria exposure and examined its spatial distribution. We found that housing quality explained large variation among households in mosquito counts. In each site, there was evidence for hot and cold spots, spatial patterns associated with urbanicity, elevation, or other environmental covariates. We also found some differences in the hotspots in rainy vs. dry seasons or before vs. after control. This work identified methods for quantifying heterogeneity in malaria exposure and offered a critical evaluation of spatially targeting interventions at malaria hotspots.

ecology↗