Biology subjects

Lewis, A. G.

Publications and source records attributed to Lewis, A. G..

5 recordsLinked to original sources

bioRxiv2025

Electron transport chain disruption leads to failure of glucose derepression via the Snf1/AMPK pathway

When Saccharomyces cerevisiae cells transition from a glucose-rich environment to low glucose conditions, the expression of genes that were previously repressed by glucose is derepressed, enabling the cell to adapt metabolic processes to the available carbon source. The Snf1 pathway is one of the primary signaling pathways responsible for orchestrating glucose sensing and signaling. In this study, we investigate the impact of disrupted electron transport chain (ETC) function, a mitochondrial protein complex essential for respiratory energy generation, in glucose derepression. We observe that respiratory incompetent mutants exposed to glucose are unable to subsequently utilize galactose as a carbon source in minimal media. In contrast, ETC mutants that have been generated and maintained on galactose can effectively continue to metabolize galactose until glucose exposure. We define this phenomenon as a Failure of Glucose Derepression (FGD), wherein respiratory incompetent cells fail to fully reverse glucose repressed gene expression regulation. Through further characterization, we show how irregular localization patterns of crucial proteins within the Snf1 pathway are associated with FGD suggesting a potential novel connection between the ETC and the Snf1 pathway during carbon source transition. SIGNIFICANCE STATEMENTO_LIRespiratory incompetent electron-transport chain mutants are capable of metabolizing galactose as a carbon source. However, when ETC mutants encounter glucose, they lose this ability to metabolize galactose. C_LIO_LIThis study demonstrates that failure to derepress glucose repressed genes facilitated by the Snf1/AMPK pathway is primarily responsible for this phenotype in ETC mutants. C_LIO_LIThese results illustrate a novel signaling role for the ETC and suggest a possible metabolic intervention to certain disease phenotypes. C_LI

cell biology↗

bioRxiv2023

Fractionating difficulty during sentence comprehension using functional neuroimaging

Sentence comprehension is highly practiced and largely automatic, but this belies the complexity of the underlying processes. We used functional neuroimaging (fMRI) to investigate garden-path sentences that cause difficulty during comprehension, in order to unpack the different processes used to support sentence interpretation. By investigating garden-path and other types of sentences within the same individuals, we functionally profiled different regions within the temporal and frontal cortices in the left hemisphere. The results revealed that different aspects of comprehension difficulty are handled by left posterior temporal, left anterior temporal, ventral left frontal, and dorsal left frontal cortices. The functional profiles of these regions likely lie along a spectrum of specificity to generality, including language-specific processing of linguistic representations, more general conflict resolution processes operating over linguistic representations, and processes for handling difficulty in general. These findings suggest that difficulty is not unitary and that there is a role for a variety of linguistic and non-linguistic processes in supporting comprehension.

neuroscience↗

bioRxiv2023

Calorie Restriction Outperforms Bariatric Surgery in a Murine Model of Obesity and Triple-Negative Breast Cancer

Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity- driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesitys procancer effects.

cancer biology↗

bioRxiv2022

Naturalistic language comprehension is supported by alpha and beta oscillations linked to domain-general inhibition and reactivation

Brain oscillations are prevalent in all species and are involved in numerous perceptual operations. Alpha oscillations are thought to facilitate processing through the inhibition of task-irrelevant networks, while beta oscillations are linked to the reactivation of content representations. Can the proposed functional role of alpha and beta oscillations be generalized from low-level operations to higher-level cognitive processes? Here we address this question focusing on naturalistic spoken language processing. Twenty-two (18 female) Dutch native speakers listened to stories in spoken Dutch and French while magnetoencephalography (MEG) was recorded. We used dependency parsing to identify three dependency states at each word, as the number of (1) newly opened dependencies, (2) dependencies that remained open, and (3) resolved dependencies. We then constructed linear forward models to predict alpha and beta power from the dependency features. Results showed that dependency features predict alpha and beta power in language-related regions beyond low-level linguistic features. Left temporal, fundamental language regions are involved in language comprehension in the alpha band, while frontal and parietal, higher-order language regions, and motor regions are mostly involved in the beta band. Critically, alpha and beta band dynamics seem to subserve language comprehension tapping into syntactic structure building and semantic composition by providing low-level mechanistic operations for inhibition and reactivation processes. Overall, this study sheds light on the role of alpha and beta oscillations during naturalistic language processing, providing evidence for the generalizability of these dynamics from perceptual to complex linguistic processes. Significance StatementPrior research identified the functional role of alpha and beta oscillations in basic perceptual and motor functions. However, it remains unclear whether their proposed role can be generalized to higher-level processes during language comprehension. Here, we found that high-level syntactic features predict alpha and beta power in language-related regions beyond low-level linguistic features when listening to comprehensible naturalistic speech. Our work contributes to the debate about whether the functional roles of brain oscillations are domain-general or depend on the task at hand. We offer experimental findings that integrate a neuroscientific framework on the role of brain oscillations as "building blocks" with language comprehension as a compositional process, and novel evidence regarding the encoding of higher-level syntactic operations in the brain. This supports the view of a domain-general role of cortical oscillations across the hierarchy of cognitive functions, from low-level sensory operations to complex linguistic processes.

neuroscience↗

bioRxiv2021

Physiological roles of short-chain and long-chain menaquinones (vitamin K2) in Lactococcus cremoris

Lactococcus cremoris and L. lactis are well-known for their occurrence and applications in dairy fermentations, but their niche extends to a range of natural and food production environments. L. cremoris and L. lactis produce MKs (vitamin K2), mainly as the long-chain forms represented by MK-9 and MK-8, and a detectable amount of short-chain forms represented by MK-3. The physiological significance of the different MK forms in the lifestyle of these bacterial species has not been investigated extensively. In this study, we used L. cremoris MG1363 to construct mutants producing different MK profiles by deletion of genes encoding (i) a menaquinone-specific isochorismate synthase, (ii) a geranyltranstransferase and (iii) a prenyl diphosphate synthase. These gene deletions resulted in (i) a non-MK producer ({Delta}menF), (ii) a presumed MK-1 producer ({Delta}ispA) and (iii) a MK-3 producer ({Delta}llmg_0196), respectively. By examining the phenotypes of the MG1363 wildtype strain and respective mutants, including biomass accumulation, stationary phase survival, oxygen consumption, primary metabolites, azo dye/copper reduction, and proteomes, under aerobic, anaerobic and respiration-permissive conditions, we could infer that short-chain MKs like MK-1 and MK-3 are preferred to mediate extracellular electron transfer and reaction with extracellular oxygen, while the long-chain MKs like MK-9 and MK-8 are more efficient in aerobic respiratory electron transport chain. The different electron transfer routes mediated by short-chain and long-chain MKs likely support growth and survival of L. cremoris in a range of (transiently) anaerobic and aerobic niches including food fermentations, highlighting the physiological significance of diverse MKs in L. cremoris.

microbiology↗