Biology subjects

Hall, A. M.

Publications and source records attributed to Hall, A. M..

5 recordsLinked to original sources

bioRxiv2024

Excitoprotective effects of conditional tau reduction in excitatory neurons and in adulthood

Tau reduction is a promising therapeutic strategy for Alzheimers disease. In numerous models, tau reduction via genetic knockout is beneficial, at least in part due to protection against hyperexcitability and seizures, but the underlying mechanisms are unclear. Here we describe the generation and initial study of a new conditional Tauflox model to address these mechanisms. Given the protective effects of tau reduction against hyperexcitability, we compared the effects of selective tau reduction in excitatory or inhibitory neurons. Tau reduction in excitatory neurons mimicked the protective effects of global tau reduction, while tau reduction in inhibitory neurons had the opposite effect and increased seizure susceptibility. Since most prior studies used knockout mice lacking tau throughout development, we crossed Tauflox mice with inducible Cre mice and found beneficial effects of tau reduction in adulthood. Our findings support the effectiveness of tau reduction in adulthood and indicate that excitatory neurons may be a key site for its excitoprotective effects. SUMMARYA new conditional tau knockout model was generated to study the protective effects of tau reduction against hyperexcitability. Conditional tau reduction in excitatory, but not inhibitory, neurons was excitoprotective, and induced tau reduction in adulthood was excitoprotective without adverse effects.

neuroscience↗

bioRxiv2022

Monoacylglycerol O-acyltransferase 1 is required for adipocyte differentiation in vitro but does not affect adiposity in mice

ObjectiveMonoacylglycerol O-acyltransferase 1 (Mogat1), a lipogenic enzyme that converts monoacylglycerol to diacylglycerol, is highly expressed in adipocytes and may regulate lipolysis by re-esterifying fatty acids released during times when lipolytic rates are low. However, the role of Mogat1 in regulating adipocyte fat storage during differentiation and diet-induced obesity is relatively understudied. MethodsHere we generated adipocyte-specific Mogat1 knockout mice and subjected them to a high-fat diet to determine the effects of Mogat1 deficiency on diet-induced obesity. We also used Mogat1 floxed mice to develop preadipocyte cell lines wherein Mogat1 could be conditionally knocked out to study adipocyte differentiation in vitro. ResultsIn preadipocytes, we found that Mogat1 knockout at the onset of preadipocyte differentiation prevented the accumulation of glycerolipids and reduced the differentiation capacity of preadipocytes. However, the loss of adipocyte Mogat1 did not affect weight gain or fat mass induced by high-fat diet in mice. Furthermore, loss of Mogat1 in adipocytes did not affect plasma lipid or glucose concentrations or insulin tolerance. ConclusionsThese data suggest Mogat1 may play a role in adipocyte differentiation in vitro but not adipose tissue expansion in response to nutrient overload in mice. STUDY IMPORTANCEO_ST_ABSWhat is already known?C_ST_ABSO_LIAdipose tissue expansion through adipocyte precursor cell differentiation is critical for proper lipid storage during nutrient overload. C_LIO_LIMonoacylglycerol O-acyltransferase 1 (Mogat1), a lipogenic enzyme, is highly induced during adipocyte differentiation of human and mouse precursor cells and is reduced in patients with obesity and metabolic dysfunction. C_LI What does this study add?O_LIMogat1 deletion during early adipocyte differentiation reduces differentiation capacity, adipogenic gene expression and lowers glycerolipid content of differentiated adipocytes. C_LIO_LIAdipocyte Mogat1 expression is dispensable for adiposity and metabolic outcomes high-fat fed mice and suggests compensation from other glycerolipid synthesis enzymes. C_LI How might these results change the direction of research?O_LIUnderstanding the molecular mechanisms of glycerolipid metabolism healthy adipose tissue expansion. C_LI

molecular biology↗

bioRxiv2021

Development and evaluation of a decision prediction tool for the reduction of fungicide applications for the control of strawberry powdery mildew epidemics

Strawberry powdery mildew (Podosphaera aphanis) causes serious losses in UK crops, potentially reducing yields by as much as 70%. Consequently, conventional fungicide application programmes tend to recommend a prophylactic approach using insurance sprays, risking the development of fungicide insensitivity and requiring careful management relative to harvest periods to avoid residual fungicides on harvested fruit. This paper describes the development of a prediction system to guide the control of P. aphanis by the application of fungicides only when pathogen infection and disease progression are likely. The system was developed over a 15-year period on commercial farms starting with its establishment, validation and then deployment to strawberry growers. This involved three stages: 1. Identification and validation of parameters for inclusion in the prediction system (2004-2008). 2. Development of the prediction system in compact disc format (2009-2015). 3. Development and validation of the prediction system in a web-based format and cost-benefit analysis (2016-2020). The prediction system was based on the temporal accumulation of conditions (temperature and relative humidity) conducive to the development of P. aphanis, which sporulates at 144 accumulated disease-conducive hours. Sensitivity analysis was performed to refine the prediction system parameters. Field validation of the results demonstrated that to effectively control disease, the application of fungicides was best done between 125 and 144 accumulated hours of disease-conducive conditions. A cost-benefit analysis indicated that, by comparison with the number and timing of fungicide applications in conventional insurance disease control programmes, the prediction system enabled good disease control with significantly fewer fungicide applications (between one and four sprays less) (df=7, t=7.6, p=0.001) and reduced costs (savings between {pound}35-{pound}493/hectare) (df=7, t=4.0, p=0.01) for the growers.

plant biology↗

bioRxiv2020

Antisense oligonucleotides against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1

ObjectiveMonoacylglycerol acyltransferase (MGAT) enzymes catalyze the synthesis of diacylglycerol from monoacylglycerol. Previous work has suggested the importance of MGAT activity in the development of obesity-related hepatic insulin resistance. Indeed, antisense oligonucleotide (ASO)-mediated knockdown of the gene encoding MGAT1, Mogat1, reduced hepatic MGAT activity and improved glucose tolerance and insulin resistance in high fat diet (HFD) fed mice. However, recent work has suggested that some ASOs may have off-target effects on body weight and metabolic parameters via activation of the interferon alpha/beta receptor 1 (IFNAR-1) pathway. MethodsMice with whole-body Mogat1 knockout or a floxed allele for Mogat1 to allow for liver-specific Mogat1-knockout (by either a liver-specific transgenic or adeno-associated virus-driven Cre recombinase) were generated. These mice were placed on a high fat diet and glucose metabolism and insulin sensitivity was assessed after 16 weeks on diet. In some experiments, mice were treated with control or Mogat1 or control ASOs in the presence or absence of IFNAR-1 neutralizing antibody. ResultsGenetic deletion of hepatic Mogat1, either acutely or chronically, did not improve hepatic steatosis, glucose tolerance, or insulin sensitivity in HFD-fed mice. Furthermore, constitutive Mogat1 knockout in all tissues actually exacerbated HFD-induced weight gain, insulin resistance, and glucose intolerance on a HFD. Despite markedly reduced Mogat1 expression, liver MGAT activity was unaffected in all knockout mouse models. Mogat1 overexpression hepatocytes increased liver MGAT activity and TAG content in low-fat fed mice, but did not cause insulin resistance. Interestingly, Mogat1 ASO treatment improved glucose tolerance in both wild-type and Mogat1 null mice, suggesting an off target effect. Inhibition of IFNAR-1 did not block the effect of Mogat1 ASO on glucose homeostasis. ConclusionThese results indicate that genetic loss of Mogat1 does not affect hepatic MGAT activity or metabolic homeostasis on HFD and show that Mogat1 ASOs improve glucose metabolism through effects independent of targeting Mogat1 or activation of IFNAR-1 signaling. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/238535v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@18d43c4org.highwire.dtl.DTLVardef@15c1974org.highwire.dtl.DTLVardef@18b396dorg.highwire.dtl.DTLVardef@16745bf_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMogat1 liver-specific KO or KD does not improve metabolism in HFD fed mice. C_LIO_LIWhole-body Mogat1-deletion impairs insulin tolerance in HFD fed mice. C_LIO_LIMogat1 ASOs improves whole body metabolism independently of gene knockdown. C_LIO_LIBlockade of the INFR response does not prevent off-target effects of Mogat1 ASOs. C_LI

physiology↗

bioRxiv2018

NRSF-mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

Repression of target genes by the transcriptional repressor neuronal restrictive silencing factor (NRSF)/repressor element 1 silencing transcription factor (REST) contributes to enduring plasticity in the developing brain. However, the cofactor(s) interacting with NRSF to enable target gene repressor are not well understood, and may vary among neuronal populations and brain regions as well as with different contexts. Here we employed the novel designer drug mS-11 to block the interactions of the cofactor Sin3 with NRSF. We tested if NRSF-Sin3 interaction is required for repression of NRSF target genes in developing hypothalamus after activity-dependent modulation of NRSF function. In the hypothalamus in vitro, blocking glutamatergic neurotransmission robustly increased NRSF binding to the target gene Crh, resulting in its repression. Blocking the binding of NRSF to the chromatin with decoy NRSE-oligodeoxynucleotides abrogated this repression. In contrast, mS-11 at several concentrations did not impede Crh repression. NRSF-mediated repression may underlie disease processes such as the onset of epilepsy. Therefore, identifying small-molecule antagonists of NRSF is crucial for the development of disease-preventing or modifying interventions.

neuroscience↗