Biology subjects

Phillips, L.

Publications and source records attributed to Phillips, L..

10 recordsLinked to original sources

bioRxiv2026

Systematic Quantitative Proteomics Defines Age, Sex, and Region-Dependent Remodeling of Lung Extracellular Matrix

The lung extracellular matrix (ECM) governs tissue architecture, mechanics, and function, yet how it remodels with age across sex and anatomical regions remains poorly understood. Here, we performed a systematic multi-factor proteomic analysis of rat lungs to define age-, sex-, and region-dependent remodeling across the tissue landscape. Age emerged as the dominant source of variation, with a conserved aging signature modified by region- and sex-specific effects. Young lungs showed coordinated ECM assembly, balanced proteolysis, and active biosynthetic programs consistent with structural adaptability and mechanical resilience. In contrast, aged lungs exhibited accumulation of mature collagen crosslinks and a more stabilized matrix architecture, indicating progressive matrix maturation and reduced structural plasticity. These changes were accompanied by proteomic signatures of metabolic stress and immune activation, suggesting coordinated remodeling across ECM, metabolic, and immune pathways during lung aging. Aging effects varied across anatomical regions and were more pronounced in females, highlighting context-dependent trajectories within the broader aging program. Age also partially reshaped spatial proteomic heterogeneity across lung compartments. Together, these findings identify matrix stabilization as a central feature of lung aging that links structural remodeling to metabolic-inflammatory imbalance and increased pulmonary vulnerability.

biochemistry↗

bioRxiv2026

RNA-binding proteins activate transcription through defined molecular grammars

Transcription factors (TFs) regulate gene expression through interactions with DNA, RNA, and proteins. RNA-binding proteins (RBPs) also assemble near regulatory elements and mediate RNA processing, yet their perturbation causes transcriptional defects. Here, we find select RBPs activate transcription through latent activation domains akin to TFs. RBP activators regulate distinct genes and interact with transcriptional condensates. Their activation domains are enriched in aromatic and polar residues but depleted of basic residues - essential features that are conserved and partially mimic TF activation domains. We validated additional RBP activators across the human proteome based on this molecular grammar, including the C-terminal domain (CTD) of RPB1, the catalytic subunit of RNA polymerase II. RPB1-CTD activates transcription by recruiting coactivators, demonstrating a non-enzymatic function in transcriptional regulation. These findings position RBPs and RPB1 as transcriptional regulators, explain coupling between transcription and RNA processing, and reveal RNA-RBP regulatory networks that parallel DNA-TF networks.

molecular biology↗

bioRxiv2024

An operational framework to map Essential Life Support Areas (ELSAs) for biodiversity, climate, and sustainable development

Almost all countries are making increasingly bold commitments to halt and reverse biodiversity loss, minimise the impacts of climate change, and transition to more sustainable development. The effective achievement of many of these commitments relies on integrated spatial planning frameworks that are adaptable to national circumstances, priorities and capabilities. This need is formally recognized by Target 1 of the Kunming-Montreal Global Biodiversity Framework (GBF), which specifies that all areas should be under such planning. Here, we describe the development and application of an operational framework for national-level integrated spatial planning: Essential Life Support Areas (ELSAs). This framework facilitates the identification of areas that - if protected, restored, or sustainably managed - can support the achievement of national commitments to biodiversity, climate, and sustainable development. The process of mapping ELSAs relies heavily on leadership by national experts and stakeholders and the integration of spatial data using systematic conservation planning tools. We showcase the ELSA process carried out for Ecuador, where the use of real-time scenario analyses enabled diverse stakeholder groups to collaborate to assess national priorities for nature, climate, and sustainable development, view trade-offs and synergies, and arrive at a spatial plan to guide national action. ELSA presented an actionable approach for Ecuador, and 12 other pilot countries, to create a spatial plan aimed at fulfilling their national and international commitments to nature, including to the GBF.

ecology↗

bioRxiv2024

Agrobacterium-mediated Cuscuta campestris transformation as a tool for understanding plant-plant interactions

Cuscuta campestris, a stem parasitic plant, has served as a valuable model plant for the exploration of plant-plant interactions and molecular trafficking. However, a major barrier to C. campestris research is that a method to generate stable transgenic plants has not yet been developed. Here, we describe the development of a Cuscuta transformation protocol using various reporter genes (GFP, GUS, or RUBY) and morphogenic genes (CcWUS2 and CcGRF/GIF), ultimately leading to a robust protocol for Agrobacterium-mediated C. campestris transformation. The stably transformed and regenerated RUBY C. campestris plants produced haustoria, the signature organ of parasitic plants, and these were functional in forming host attachments. The locations of T-DNA integration in the parasite genome were confirmed through TAIL-PCR. Transformed C. campestris also produced flowers and transgenic seeds exhibiting betalain pigment, providing proof of germline transmission of the RUBY transgene. Furthermore, the RUBY reporter is not only a useful selectable marker for the Agrobacterium-mediated transformation, but also provides insight into the movement of molecules from C. campestris to the host during parasitism. Thus, the protocol for transformation of C. campestris reported here overcomes a major obstacle to Cuscuta research and opens new possibilities for studying parasitic plants and their interactions with hosts.

plant biology↗

bioRxiv2023

Memory control deficits in the sleep-deprived human brain

Sleep disturbances are associated with intrusive memories, but the neurocognitive mechanisms underpinning this relationship are poorly understood. Here, we show that an absence of sleep disrupts prefrontal inhibition of memory retrieval, and that the overnight restoration of this inhibitory mechanism is predicted by time spent in rapid eye movement (REM) sleep. The functional impairments arising from sleep loss are linked to a behavioural deficit in the ability to suppress unwanted memories, and coincide with a deterioration of deliberate patterns of self-generated thought. We conclude that sleep deprivation gives rise to intrusive memories via the disruption of neural circuits governing mnemonic inhibitory control, which may rely on REM sleep.

neuroscience↗

bioRxiv2023

A Brain Model of Disturbed Self-Appraisal in Social Anxiety Disorder

The brains default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, including social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modelling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, in the absence of task modulation, SAD participants exhibited reduced intrinsic connectivity, with reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD.

neuroscience↗

bioRxiv2022

Mortality without springing a leak: Locust gut epithelia do not become more permeable to fluorescent dextran and bacteria in the cold

The insect gut, which plays a role in ion and water balance, has been shown to leak solutes in the cold. Cold stress can also activate insect immune systems, but it is unknown if the leak of the gut microbiome is a possible immune trigger in the cold. We developed a novel feeding protocol to load the gut of locusts (Locusta migratoria) with fluorescent bacteria before exposing them to -2{degrees}C for up to 48 h. No bacteria were recovered from the hemolymph of cold-exposed locusts, regardless of exposure duration. To examine this further, we used an ex vivo gut sac preparation to re-test cold-induced fluorescent FITC-dextran leak across the gut and found no increased rate of leak. These results question not only the validity of FITC-dextran as a marker of paracellular barrier permeability in the gut, but also to what extent the insect gut becomes leaky in the cold.

physiology↗

bioRxiv2021

Biallelic loss-of-function OBSCN variants predispose individuals to severe, recurrent rhabdomyolysis

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, the majority of cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) co-segregating with disease. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

genetics↗

bioRxiv2020

A Novel Machine Learning Approach Uncovers New and Distinctive Inhibitors for Cyclin-Dependent Kinase 9

We present a novel combination of generative and predictive machine learning models for discovering unique protein inhibitors. The new method is assessed on its ability to generate unique inhibitors for the cancer associated protein kinase, CDK9. We validate our method by performing biochemical assays, attaining a hit rate of more than 10%, demonstrating the method to be a notable improvement upon a more standard, and somewhat naive approach. Moreover, we imposed the additional challenge of finding inhibitors that are readily synthesized. Importantly, two new inhibitors are found, with one being distinct from reported CDK9 inhibitors. We discuss the results in the context of modern machine learning principles and the desire expressed by the rational drug design community to secure molecules that are structurally different, yet with high binding affinities, to structurally determined protein targets.

bioinformatics↗

bioRxiv2017

Identification Of A Native Novel Oncolytic Immunoglobulin On Exfoliated Colon Epithelial Cells: A Bispecific Heterodimeric Chimera Of IgA/IgG

Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (SCSR-010 Fecal Cell Isolation Kit, NonInvasive Technologies, Elkridge, MD), preserved at room temperature for up to one week, with viability of >85% and low levels of apoptosis (8% - 10%) exhibit two distinct cell size subpopulations, in the 2.5M- 5.0 M and 5.0M-8.0M range. In addition to IgA, about 60% of the cells expressed a novel heterodimeric IgA/IgG immunoglobulin that conferred a broad-spectrum cell mediated cytotoxicity against tumor cells. In a cohort of 58 subjects the exclusive absence of this immunoglobulin in two African-Americans was suggestive of a germline deletion. Serial cultures in stem cell medium retained the expression of this heterodimer. Since a majority of the cystic cells expressed the stem cell markers Lgr5 and Musashi-1 we termed these cells as gastrointestinal progenitor stem cells (GIP-C**). CXCR-4, the cytokine co-receptor for HIV was markedly expressed. These cells also expressed CD20, IgA, IgG, CD45, and COX-2. We assume that they originated from mature columnar epithelium by dedifferentiation. Our observations indicate that we have a robust noninvasive method to study mucosal pathophysiology and a direct method to create a database for applications in regenerative medicine.

cell biology↗