Biology subjects

Norris, M.

Publications and source records attributed to Norris, M..

7 recordsLinked to original sources

bioRxiv2025

Inclusion of JNK-independent drugs within multi-agent chemotherapy improves response in relapsed high-risk neuroblastoma

The acquisition of a chemoresistant state underlies poor prognosis in many cancers, including neuroblastoma. We previously demonstrated that heterogeneity in apoptosis induction through c-Jun N-Terminal Kinase (JNK) promotes a form of non-genetic chemoresistance in neuroblastoma observable at both patient and single-cell levels. As the maintenance of this JNK-impaired state in the relapse setting is a significant barrier to the efficacy of many standard-of-care chemotherapy drugs, we combined a mechanistic, mathematical model of JNK activation with a paediatric focused drug screen and identified approved oncology drugs capable of inducing apoptosis in a JNK-independent manner. Functional genomics further revealed that synergy between these JNK-independent drugs and standard-of-care chemotherapies emerged from differential utilisation of apoptotic network components, rather than from their direct mechanistic targets. Efficacy studies with PDX models also confirmed that including a JNK-independent drug within existing chemotherapy backbones significantly improved response in the relapse setting, where new approaches are urgently needed. One Sentence SummaryDrug combinations utilising differential sets of network components can overcome the apoptotic impaired state of relapsed high-risk neuroblastoma.

cancer biology↗

bioRxiv2024

Anxiety-related attentional changes and their relation to freezing of gait in people with Parkinson's: a cross validation of the Adapted Gait Specific Attentional Profile (G-SAPa)

BACKGROUNDAnxiety often exacerbates freezing of gait (FOG) in people with Parkinsons (PwP). Research shows that anxiety-related attentional processes and associated processing inefficiencies, such as conscious movement processing (CMP) and ruminations, can substantially impact movement control. However, the impact of these attentional characteristics on FOG remains largely unexplored. OBJECTIVESTo (i) validate an adapted 10-item (1-5 Likert scale) Gait-Specific Attentional Profile in PwP (G-SAP-PD), and (ii) assess if G-SAP-PD-subscales (Physiological Arousal, CMP, Rumination, and Processing Inefficiencies) are associated with self-reported FOG frequency. METHODSWe recruited 440 PwP (Mage=65.5{+/-}8.7; 5.8{+/-}5.0 years since diagnosis) across the UK. Participants completed the G-SAP-PD, and questions on demographics, medical background, and FOG frequency (scale of 0: "never freeze" to 4: "every day"). We assessed G-SAP-PDs internal consistency (alpha), structural validity (confirmatory factor analysis), and subscale scores associations with FOG frequency (ordinal regression). RESULTSThe G-SAP-PDs showed high internal consistency (>0.61) and acceptable/good model fit (comparative fit index=0.976). Physiological Arousal and CMP subscale scores were less strongly correlated for PwP with FOG (PwP+FOG, r=.52, p=0.001) compared to (PwP-FOG, r=.79; p=0.001). Higher Rumination (OR: 1.323, 95%CI: [1.214-1.440]) and Physiological Arousal (OR: 1.195, 95%CI: [1.037-1.377]) were significantly associated with higher FOG frequency, when controlling for age, time since diagnosis and balance/gait problems. CONCLUSIONSThe G-SAP-PD is a reliable and convenient tool to measure and identifying potentially maladaptive anxiety-related attentional processes that might impact FOG. Our data suggests a relative inability of PwP+FOG to engage in compensatory goal-directed attentional focus. Further study is warranted. Plain Language SummaryAnxiety can worsen freezing of gait in people with Parkinsons. It often leads to worrisome thoughts, and influences how people pay attention to their walking. We think that these changes in attention can substantially influence peoples movement - for better or worse. However, there is a lack of research on this topic, and reliable assessment tools are missing. Therefore, we tested if we could assess changes in the thoughts and attention of people with Parkinsons, using a questionnaire (Gait-Specific Attentional Profile (G-SAP-PD)), previously used in older adults without Parkinsons. This questionnaire aims to measure peoples perception of their physiological arousal (how anxious they feel), conscious movement (attention they direct to walking), rumination (worrisome thoughts), and thinking efficiency (the ability to focus on different tasks). We also investigated if people who experience freezing show different attentional characteristics compared to people who do not experience freezing. Four-hundred and forty people with Parkinsons filled the G-SAP-PD questionnaire. We confirmed the questionnaires reliability, and found that people who indicated to have more worrisome thoughts and greater physiological arousal also experienced freezing more often. Our findings suggest that people with Parkinsons who experience freezing were less able to consciously direct attention to the task at hand (taking a step) when experiencing high physiological arousal. The G-SAP-PD represents a short and convenient tool for identifying potentially negative attentional and thinking processes that may increase freezing frequency. With further research it could be used as a predictive tool and provide possible novel treatments to reduce freezing frequency.

neuroscience↗

bioRxiv2021

Assessing student success in a Peer Assisted Learning program using propensity score matching

The Peer Assisted Learning program at Sacramento State University (PAL) was established in 2012 with one section supporting introductory chemistry. It now serves 17 gatekeeper courses in Biology, Chemistry, Mathematics, Physics, and Statistics, enrolling approximately 1,400 students annually. Adapting the Peer-Led Team Learning model, PAL Facilitators do not teach, tutor, or even confirm answers; they do ask scaffolding questions, provide encouragement, and ensure that all group members participate in problem-solving. Here we assess the efficacy of the program in terms of student success in the parent course. As PAL is an opt-in program, we employ propensity score matching techniques to account for confounding factors. Our analysis of 11 classes shows that PAL provides an average course GPA bump ranging from .23 to .71 grade points (mean .42). Compared to the non-PAL baseline course GPA, this amounts to an increase of 9% to 51% (mean 23%). We consider data from over 25,000 students, and our propensity score analysis uses over 10,000 students (4,519 PAL, 5,814 non-PAL) for whom appropriate matches could be found.

scientific communication and education↗

bioRxiv2020

Feeding Experimentation Device version 3 (FED3): An open-source home-cage compatible device for measuring food intake and operant behavior

Feeding is critical for survival and disruption in the mechanisms that govern food intake underlie disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation: The Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs. In this paper we demonstrate the utility of FED3 in a range of experimental paradigms. In BriefUsing a novel, high-throughput home cage feeding platform, FED3, Matikainen-Ankney et al. quantify food intake and operant learning in groups of mice conducted at multiple institutions across the globe. Results include rates of operant efficiency, circadian feeding patterns, and operant optogenetic self-stimulation. Highlights O_LIThe Feeding Experimentation Device version 3(FED3) records food intake and operant behavior in rodent home cages. C_LIO_LIAnalysis of food intake includes total intake, meal pattern analysis, and circadian analysis of feeding patterns. C_LIO_LIFED3 also allows for operant behavioral assays to examine food learning and motivation. C_LI

animal behavior and cognition↗

bioRxiv2020

Ebola and Marburg virus matrix layers are locally ordered assemblies of VP40 dimers

A key step in the life cycle of enveloped viruses is the budding of nascent virions from the host membrane. In filoviruses such as Ebola and Marburg virus, this process is achieved by the matrix protein VP40. When expressed alone, VP40 induces the budding of filamentous virus-like particles, suggesting that localization to the plasma membrane, oligomerization into a matrix layer, and the generation of membrane curvature are intrinsic properties of VP40. While a number of crystal structures of VP40 have been determined in various oligomerization states, there has been no direct information on the structure of assembled VP40 matrix layers within viruses or virus-like particles. Here, we present structures of Ebola and Marburg VP40 matrix layers in intact virus-like particles, as well as within intact Marburg viruses. We find that the matrix layers are formed from VP40 dimers which assemble into extended chains via C-terminal domain interactions. These chains stack into layers, forming a 2D lattice below the membrane surface. However, these 2D lattices are only locally ordered, forming a patchwork assembly across the membrane surfaces and suggesting that assembly may begin at multiple points. These observations define the structure and arrangement of the matrix protein layer that mediates the formation of filamentous filovirus particles.

microbiology↗

bioRxiv2019

In vivo mRNA structure regulates miRNA cleavage in Arabidopsis

MicroRNA (miRNA)-mediated cleavage is involved in numerous essential cellular pathways. miRNAs recognize target RNAs via sequence complementarity. In addition to complementarity, in vitro and in silico studies have suggested that RNA structure may influence the accessibility of mRNAs to miRNA-Induced Silencing Complexes (miRISCs), thereby affecting RNA silencing. However, the regulatory mechanism of mRNA structure in miRNA cleavage remains elusive. Here, we investigated the role of in vivo RNA secondary structure in miRNA cleavage by developing the new CAP-STRUCTURE-seq method to capture the intact mRNA structurome in Arabidopsis thaliana. This approach revealed that miRNA target sites were not structurally accessible for miRISC binding prior to cleavage in vivo. Instead, the unfolding of the target site structure is the primary determinant for miRISC activity in vivo. Notably, we found that the single-strandedness of the two nucleotides immediately downstream of the target site, named Target Adjacent structure Motif (TAM), can promote miRNA cleavage but not miRNA binding, thus decoupling target site binding from cleavage. Our findings demonstrate that mRNA structure in vivo can regulate miRNA cleavage, providing evidence of mRNA structure-dependent regulation of biological processes.

molecular biology↗

bioRxiv2019

In vivo nuclear RNA structurome reveals RNA-structure regulation of mRNA processing in plants

mRNA processing is critical for gene expression. A challenge in regulating mRNA processing is how to recognize the actual mRNA processing sites, such as splice and polyadenylation sites, when the sequence content is insufficient for this purpose. Previous studies suggested that RNA structure affects mRNA processing. However, the regulatory role of RNA structure in mRNA processing remains unclear. Here, we performed in vivo selective 2-hydroxyl acylation analysed by primer extension (SHAPE) chemical profiling on Arabidopsis nuclear RNAs and generated the in vivo nuclear RNA structure landscape. We found that nuclear mRNAs fold differently from cytosolic mRNAs. Notably, we discovered a two-nucleotide single-stranded RNA structure feature upstream of 5 splice sites that is strongly associated with splicing and the selection of alternative 5 splice sites. Moreover, we found the single-strandedness of branch point is also associated with 3 splice site recognition. We also identified an RNA structure feature comprising two close-by single-stranded regions that is specifically associated with both polyadenylation and alternative polyadenylation events. Our work demonstrates an RNA structure regulatory mechanism for mRNA processing.

plant biology↗