Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals

Comparison of growth in neutered Domestic Shorthair kittens with growth in sexually-intact cats.

The first aim of these studies was to compare growth patterns of healthy kittens neutered during growth with growth standards created for sexually-intact kittens. A second aim was to clarify the impact of neutering in kittens on body composition and body shape. Study 1 was a retrospective observational study comparing median growth trajectories of healthy, client-owned domestic shorthair (DSH) kittens in optimal body condition and neutered at different ages, with previously-created growth standards from a similar, sexually-intact, population. The neuter groups contained between 3.0k and 9.3k cats. For all neuter groups in both sexes, the median growth trajectory inclined upwards after the procedure, with this being more marked in female than in male kittens. This upwards inclination was less marked for kittens neutered later during growth in both sexes, with the effect being least in kittens neutered after 28-29 weeks. Study 2 was an analysis of new body composition and zoometric data from a previously-published randomised study, comparing growth-related measures between 11 pairs of sexually-intact and neutered (at 19 weeks age) female DSH cats in a research population. Before neutering, the growth pattern in neutered kittens and sexually-intact kittens was similar, but neutered kittens were heavier by 52 weeks (mean difference in fold change vs. 10 weeks 1.34, 95-CI: 1.07-1.72), had a greater fat mass (mean difference in fold change vs. 10 weeks 1.91, 95-CI 1.09-3.21) and greater lean mass (mean difference in fold change vs. 10 weeks 1.23, 95-CI: 1.03-1.48). Abdominal girth (mean difference in fold change vs. 10 weeks 1.20, 95-CI: 1.04-1.39) and rib cage length (mean difference in fold change vs. 10 weeks 1.18, 95-CI: 1.02-1.36) were also greater, but there were no differences in other zoometric measurements. Veterinarians should consider the potential impact that neutering has on gain of adipose tissue, especially early neutering in female kittens. Bodyweight should be monitored closely during growth and especially after neutering to prevent inappropriate weight gain

Growth standard charts for monitoring bodyweight in intact domestic shorthair kittens from the USA

The optimal growth of domesticated cats has not yet been well defined. This study first aimed to create evidence-based growth standards for healthy pet domestic shorthair (DSH) kittens, and then compare the pattern of growth curves depicted by the standards with growth patterns in other healthy DSH kittens and those with abnormal body condition. Data were derived from the clinical records of the BANFIELD® Pet Hospital (BANFIELD) network in the USA and from a research population in the UK (Waltham Petcare Science Institute, UK). A ‘modelling’ dataset was first created from the BANFIELD records, comprising bodyweight data from immature client-owned DSH cats that had remained healthy and in ideal body condition within the first 2.5y of life. This was used to construct growth centile curves for male and female kittens, covering the age range 8 to 78 weeks, using Generalised Additive Models for Location, Shape and Scale. Growth patterns depicted by the centile curves were compared with the growth patterns of healthy DSH kittens from both research colonies and kittens attending BANFIELD that were classified as overweight or underweight. Overall, there was a broad agreement to the growth standards with approximately half of the research population (206/507, 49%) staying within 2 centile lines of their starting centile, and upward and downward movements outside this range being roughly equally distributed. Compared with the growth standards, the 122 overweight BANFIELD kittens were heavier on average at the start of monitoring and subsequently grew more quickly with 63 (52%) crossing at least 2 standard centile lines upwards. Only 4 underweight DSH kittens were available in the BANFIELD database; compared with the standards, there was a marked initial dip in growth followed by subsequent catch-up growth and 2/4 kittens crossed 2 or more centile lines downwards at some point. Evidence-based growth standards are developed here for male and female sexually-intact DSH kittens. Crossing centiles in an upwards and downwards direction is associated with cats becoming overweight or underweight by early adulthood, respectively. Further work is required to determine whether the clinical use of these growth standards will improve the health and wellbeing of pet cats.</jats:p

Comparison of growth in neutered Domestic Shorthair kittens with growth in sexually-intact cats

The first aim of these studies was to compare growth patterns of healthy kittens neutered during growth with growth standards created for sexually-intact kittens. A second aim was to clarify the impact of neutering in kittens on body composition and body shape. Study 1 was a retrospective observational study comparing median growth trajectories of healthy, client-owned domestic shorthair (DSH) kittens in optimal body condition and neutered at different ages, with previously-created growth standards from a similar, sexually-intact, population. The neuter groups contained between 3.0k and 9.3k cats. For all neuter groups in both sexes, the median growth trajectory inclined upwards after the procedure, with this being more marked in female than in male kittens. This upwards inclination was less marked for kittens neutered later during growth in both sexes, with the effect being least in kittens neutered after 28–29 weeks. Study 2 was an analysis of new body composition and zoometric data from a previously-published randomised study, comparing growth-related measures between 11 pairs of sexually-intact and neutered (at 19 weeks age) female DSH cats in a research population. Before neutering, the growth pattern in neutered kittens and sexually-intact kittens was similar, but neutered kittens were heavier by 52 weeks (mean difference in fold change vs. 10 weeks 1.34, 95-CI: 1.07–1.72), had a greater fat mass (mean difference in fold change vs. 10 weeks 1.91, 95-CI 1.09–3.21) and greater lean mass (mean difference in fold change vs. 10 weeks 1.23, 95-CI: 1.03–1.48). Abdominal girth (mean difference in fold change vs. 10 weeks 1.20, 95-CI: 1.04–1.39) and rib cage length (mean difference in fold change vs. 10 weeks 1.18, 95-CI: 1.02–1.36) were also greater, but there were no differences in other zoometric measurements. Veterinarians should consider the potential impact that neutering has on gain of adipose tissue, especially early neutering in female kittens. Bodyweight should be monitored closely during growth and especially after neutering to prevent inappropriate weight gain

High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice

Maternal folic acid (FA) supplementation prior to and during gestation is recommended for the prevention of neural tube closure defects in the developing embryo. Prior studies, however, suggested that excessive FA supplementation during gestation can be associated with toxic effects on the developing organism. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects neurobehavioural development in the offspring generation. Detailed behavioural analyses showed reversal learning impairments in the Morris water maze in offspring derived from dams exposed to FD prior to conceiving. Furthermore, offspring of FD dams showed minor and transient gene expression differences relative to controls. Our data suggest that temporary exposure of female germ cells to FD is sufficient to cause impaired cognitive flexibility in the subsequent generation

An inflammatory landscape for preoperative neurologic deficits in glioblastoma

Introduction: Patients with glioblastoma (GBM), one of the most aggressive forms of primary brain tumors, exhibit a wide range of neurologic signs, ranging from headaches to neurologic deficits and cognitive impairment, at first clinical presentation. While such variability is attributed to inter-individual differences in increased intracranial pressure, tumor infiltration, and vascular compromise, a direct association with disease stage, tumor size and location, edema, and necrotic cell death has yet to be established. The lack of specificity of neurologic symptoms often confounds the diagnosis of GBM. It also limits clinicians' ability to elect treatment regimens that not only prolong survival but also promote symptom management and high quality of life. Methods: To decipher the heterogeneous presentation of neurologic symptoms in GBM, we investigated differences in the molecular makeup of tumors from patients with and without preoperative neurologic deficits. We used the Ivy GAP (Ivy Glioblastoma Atlas Project) database to integrate RNA sequencing data from histologically defined GBM tumor compartments and neurologic examination records for 41 patients. We investigated the association of neurologic deficits with various tumor and patient attributes. We then performed differential gene expression and co-expression network analysis to identify a transcriptional signature specific to neurologic deficits in GBM. Using functional enrichment analysis, we finally provided a comprehensive and detailed characterization of involved pathways and gene interactions. Results: An exploratory investigation of the association of tumor and patient variables with the early development of neurologic deficits in GBM revealed a lack of robust and consistent clinicopathologic prognostic factors. We detected significant differences in the expression of 728 genes (FDR-adjusted p-value ≤ 0.05 and relative fold-change ≥ 1.5), unique to the cellular tumor (CT) anatomical compartment, between neurologic deficit groups. Upregulated differentially expressed genes in CT were enriched for mesenchymal subtype-predictive genes. Applying a systems approach, we then identified co-expressed gene sets that correlated with neurological deficit manifestation (FDR-adjusted p-value < 0.1). Collectively, these findings uncovered significantly enriched immune activation, oxidative stress response, and cytokine-mediated proinflammatory processes. Conclusion: Our study posits that inflammatory processes, as well as a mesenchymal tumor subtype, are implicated in the pathophysiology of preoperative neurologic deficits in GBM

Median and interquartile weight by age (on the centile scale) for DSH kittens in the research colony data set.

Plots are split by sex: (a) male and (b) female. On each graph, the median is depicted by the solid green line, the interquartile range by the shaded region, and the standard centiles (0.4%, 2%, 9%, 25%, 50%, 75%, 91%, 98% and 99.6%), as calculated from the growth standard population, are shown by the grey horizontal lines (dotted, apart from 50%, which is shown as solid).</p

Fig 5 -

Density distribution of the number of standard centile lines crossed in an (a) upwards and (b) downwards direction for DSH kittens. Plots only include those with at least 3 weight measurements over 6 months in the age range 8 to 78 weeks old in the underweight subset (blue) and overweight subset (red). The vertical dotted line indicates 2 centile crossings.</p