Biology subjects

Hodges, T.

Publications and source records attributed to Hodges, T..

4 recordsLinked to original sources

bioRxiv2026

Chronic unpredictable stress induces negative cognitive bias in rats with sex-specific changes in neurogenesis and functional connectivity

Background: Females are more likely to be diagnosed with major depressive disorder (MDD) than males. Cognitive symptoms of MDD include negative cognitive bias, the perception of ambiguous situations as negative, which predicts MDD episode onset and severity. MDD is associated with changes to functional connectivity between regions involved in cognition, emotion, attention, and memory. Methods: Here we examined the impact of chronic unpredictable stress (CUS) on negative cognitive bias in male (n=18) and female (n=22) Sprague-Dawley rats. We assessed hippocampal neurogenesis and c-Fos expression in response to an ambiguous context across 15 regions of the frontal cortex, amygdala, nucleus accumbens, and hippocampus, including in newborn dentate gyrus (DG) neurons, to examine functional connectivity during cognitive bias testing. We conducted a graph-based network analysis and constructed linear models to predict freezing in the ambiguous context based on regional activation. Results: CUS-exposed rats froze more to the ambiguous context than non-CUS-exposed rats, regardless of sex. CUS decreased neurogenesis in the ventral DG of both sexes, and increased activation of new neurons in the dorsal DG of males only. In response to the ambiguous context, CUS males had an increase in c-Fos expression in the amygdala. CUS produced extensive, sex-specific network reorganization, decreasing global network efficiency in males but not in females. Freezing in the ambiguous context was predicted by activation of new neurons in combination with the ventral CA1 in opposing directions across sex. Conclusions: These findings suggest that sex-specific pathways drive the expression of CUS-induced negative cognitive bias, underscoring the necessity of sex-stratified preclinical and clinical research on negative cognitive bias in depression.

neuroscience↗

bioRxiv2025

A new corrector rescues F508del-CFTR folding through stabilization of the TMD1-NBD1 linker

While Trikafta has turned many CF patients into people that lead relatively healthy lives, additional modulators are still needed. We developed an acylsulfonamide-type C2 corrector X307810 that is potent and shows a distinctive mode of action in rescuing F508del-CFTR from degradation at the endoplasmic reticulum. We tracked the de-novo folding and assembly of each CFTR domain with a radio-active pulse chase - limited proteolysis folding assay and determined when and where X307810 works on the newly synthesized protein. X307810 rescued the Golgi form of F508del-CFTR to 80% of wild-type values. To our knowledge, such a dramatic increase has never been attained with a single corrector. Zooming in on X307810 mode of action revealed that the corrector changed protease resistance of the linker between TMD1 and NBD1 during late stages of CFTR folding. X307810 is the first corrector that added a unique new fragment to the typical limited-proteolysis pattern. Other C2 correctors do not change fragments, but portray an increase in fragment quantity characteristic of domain assembly in wild-type and corrected F508del-CFTR. X307810 instead extended protection of TMD1 from intracellular loop 2 to the unstructured regulatory insertion of NBD1. These results provide new and important insights into the impact of acylsulfonamide correctors on CFTR structure and function. SIGNIFICANCE STATEMENTCFTR is an anion channel, mutations in which cause cystic fibrosis (CF). Corrector compounds allow misfolded missense CFTR mutants to escape from degradation in the endoplasmic reticulum, which is the basis for CF therapy, in combination with a potentiator. How correctors improve folding is incompletely understood. We here report on X307810 having a novel mode of action on post-translational domain assembly of newly synthesized CFTR. Our in-cell folding assay shows that X307810 stabilizes the linker between the first transmembrane domain (TMD1) and the first nucleotide binding domain (NBD1) into the Regulatory Insertion; it strengthens the TMD1-NBD1-ICL4 interface. The action of X307810 boosts egress of F508del-CFTR from the ER to an unprecedented 80% for a single modulator.

biochemistry↗

bioRxiv2022

Automated classification of estrous stage in rodents using deep learning

The rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types. However, manual classification of epithelial cell samples is time-intensive and variable, even amongst expert investigators. Here, we use a deep learning approach to achieve classification accuracy at expert levels in a matter of seconds. Due to the heterogeneity and breadth of our input dataset, our deep learning approach ("EstrousNet") is highly generalizable across rodent species, stains, and subjects. The EstrousNet algorithm exploits the temporal dimension of the hormonal cycle by fitting classifications to an archetypal estrous cycle, highlighting possible misclassifications and flagging anestrus phases (e.g., pseudopregnancy). EstrousNet allows for rapid estrous cycle staging, improving the ability of investigators to consider endocrine state in their rodent studies.

cell biology↗

bioRxiv2020

Anomalous reverse transcription through chemical modifications in polyadenosine stretches

Thermostable reverse transcriptases are workhorse enzymes underlying nearly all modern techniques for RNA structure mapping and for transcriptome-wide discovery of RNA chemical modifications. Despite their wide use, these enzymes behaviors at chemical modified nucleotides remain poorly understood. Wellington-Oguri et al. recently reported an apparent loss of chemical modification within putatively unstructured polyadenosine stretches modified by dimethyl sulfate or 2 hydroxyl acylation, as probed by reverse transcription. Here, re-analysis of these and other publicly available data, capillary electrophoresis experiments on chemically modified RNAs, and nuclear magnetic resonance spectroscopy on A12 and variants show that this effect is unlikely to arise from an unusual structure of polyadenosine. Instead, tests of different reverse transcriptases on chemically modified RNAs and molecules synthesized with single 1-methyladenosines implicate a previously uncharacterized reverse transcriptase behavior: near-quantitative bypass through chemical modifications within polyadenosine stretches. All tested natural and engineered reverse transcriptases (MMLV; SuperScript II, III, and IV; TGIRT-III; and MarathonRT) exhibit this anomalous bypass behavior. Accurate DMS-guided structure modeling of the polyadenylated HIV-1 3 untranslated region RNA requires taking into account this anomaly. Our results suggest that poly(rA-dT) hybrid duplexes can trigger unexpectedly effective reverse transcriptase bypass and that chemical modifications in poly(A) mRNA tails may be generally undercounted.

biochemistry↗