Biology subjects

Knowles, J.

Publications and source records attributed to Knowles, J..

4 recordsLinked to original sources

bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗

bioRxiv2022

Mice lacking Ptprd exhibit deficits in goal-directed behavior and female-specific impairments in sensorimotor gating

Protein Tyrosine Phosphatase receptor type D (PTPRD) is a member of the protein tyrosine phosphatase family that mediates cell adhesion and synaptic specification. Genetic studies have linked Ptprd to several neuropsychiatric phenotypes, including Restless Leg Syndrome (RLS), opioid abuse disorder, and antipsychotic-induced weight gain. Genome-wide association studies (GWAS) of either pediatric obsessive-compulsive traits, or Obsessive-Compulsive Disorder (OCD), have identified loci near Ptprd as genome-wide significant, or strongly suggestive for this trait. We assessed Ptprd wild-type (WT), heterozygous (HT), and knockout (KO) mice for behavioral dimensions that are altered in OCD, including anxiety and exploration (open field test, dig test), perseverative behavior (splash-induced grooming, spatial d), sensorimotor gating (prepulse inhibition), and home cage goal-directed behavior (nest building). No effect of genotype was observed in any measure of the open field test, dig test, or splash test. However, Ptprd KO mice of both sexes showed impairments in nest building behavior. Finally, female, but not male, Ptprd KO mice showed deficits in prepulse inhibition, an operational measure of sensorimotor gating that is reduced in female, but not male, OCD patients. Our results indicate that constitutive lack of Ptprd may contribute to the development of certain domains that are altered OCD, including goal-directed behavior, and reduced sensorimotor gating specifically in females.

neuroscience↗

bioRxiv2022

Cell type catalog of middle turbinate epithelium

ImportanceElucidation of the cellular makeup of the middle turbinate provides a foundation for future studies of pathogenesis of sinonasal disease. Neural progenitors and pluripotent basal cells found in middle turbinate mucosa potentially can be used to develop cellular models to study brain disorders or in regenerative medicine to substitute neuronal tissues. ObjectiveSingle cell RNA-sequencing (scRNA-seq) of middle turbinate mucosa was performed to create the first single cell transcriptome catalog of this part of the human body. DesignSamples were obtained from the head of the middle turbinate from healthy volunteers. After the specimen was prepared per lab protocol, cells were dissociated, suspended, and counted. Single cell libraries were then prepared according to the 10x Genomics protocol and sequenced using NovaSeq 6000 (Illumina). Sequencing data were processed using Cell Ranger, and clustering and gene expression analysis was performed using Seurat. Cell types were annotated using known markers and data from other single cell studies. SettingSingle center, tertiary care center ParticipantsHealthy volunteer Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)None Main Outcome(s) and Measure(s)Identification of cell types of middle turbinate mucosa through expression profiling of single cells using known markers Results14 unique cell types were identified, including serous, goblet, club, basal, ciliated, endothelial, and neural progenitor cells, as well as multiple types of blood cells. Conclusions and RelevanceThis catalog provides a comprehensive depiction of the cellular composition of middle turbinate mucosa. By uncovering the cellular stratification of gene expression profiles in healthy middle turbinate epithelium, the groundwork has been laid for further investigation into the molecular pathogenesis and targeted therapy of sinonasal disease. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the cellular makeup of human middle turbinate mucosa? FindingsSingle-cell RNA sequencing revealed 14 cell types in middle turbinate epithelium, including neural progenitors, a previously unrecognized component of middle turbinate epithelium. MeaningGene expression profiles of middle turbinate mucosa cell types are concordant with other respiratory mucosa transcriptomic data with notable heterogeneity in serous and basal cells.{square}

genomics↗

bioRxiv2020

Modelling the contribution of iodised salt in industrially processed foods to iodine intake in Macedonia

Evidence from the 1950s showed that Macedonia was iodine deficient. After the introduction of mandatory universal salt iodisation, the country saw a steady increase in iodine intake and decline in goitre prevalence, earning iodine-deficiency free status in 2003. Iodine status assessments in 2007 and 2016 showed adequate iodine intake among school age children (median urinary iodine concentration of 241 {micro}g/L and 236 {micro}g/L respectively). Macedonia participated in the 2019 piloting of the Iodine Global Network Programme Guidance on the use of iodised salt in industrially processed foods to better understand salt and iodised salt intake from food sources other than household salt. Aggregated data from the 2017 Household Consumption and Expenditure Survey (HCES) was used to determine household salt consumption, to identify widely-consumed, salt-containing industrially processed foods and estimate typical daily intake of these foods. The salt content of these foods was estimated using national standards and the Danish food composition database. The percentage of this salt that was iodised was assessed using customs data for salt imports. Although the study has its limitations, including a relatively small selection of foods, the results indicate potential iodine intake from iodised household salt and iodised salt in the selected foods of above 300% of the Estimated Average Requirement and over 220% of the Recommended Nutrient Intake for adults. This was approximately 50% of the tolerable safe Upper Level for iodine intake. The study confirmed high daily salt intake (11.2 grams from household salt only). Successful salt reduction would be expected to reduce iodine intake, however, modelling with 10% and 30% reduction implied this is unlikely to put any population group at risk of deficiency. It is recommended that design and implementation of salt iodisation and salt reduction policies are harmonized, alongside continued regular iodine status monitoring for different population groups.

physiology↗