Biology subjects

Carr, J.

Publications and source records attributed to Carr, J..

8 recordsLinked to original sources

bioRxiv2025

Physics-Informed Digital Twin Can Predict Cerebral Blood Flow and Cerebral Vascular Regulation Mechanisms in Neurocritical Care Patients

1Cerebral blood flow is vital for brain function and is acutely controlled through a set of physiological mechanisms known as cerebral vascular regulation (CVR)[1-3]. It remains challenging to directly measure the dynamics and function of individual CVR mechanisms[4], limiting our ability to understand and optimize brain perfusion, particularly for neurologically injured patients. Digital twins offer an ideal tool for overcoming this gap because they enable estimation, tracking, and forecasting of unmeasured physiological states[5, 6]. Here, we introduce CereBRLSIM (Cerebral Blood Regulation Latent State Inference and Modeling), a digital twin that integrates physiological knowledge and patient data to infer CVR function and predict cerebral dynamics. Using both in vivo experiments and simulated data, CereBRLSIM predicted cerebral hemodynamics with high accuracy and estimated the dynamics of myogenic, endothelial, and metabolic mechanisms underlying CVR. When personalized to neurocritical care patient data, CereBRLSIM differentiated cerebral hemodynamic phenotypes, predicted patient outcomes, and forecasted blood flow with significantly higher accuracy than machine learning models. This work provides a novel, interpretable, and clinically compatible approach for quantifying CVR function and forecasting cerebral blood flow, enabling new opportunities in precision diagnostics and foundational understanding of cerebral hemodynamics.

bioengineering↗

bioRxiv2024

A novel ilarvirus protein is expressed via stop codon readthrough and suppresses RDR6-dependent RNA silencing

Ilarviruses are a relatively understudied but important group of plant RNA viruses that includes a number of crop pathogens. Their genomes comprise three RNA segments encoding two replicase subunits, movement protein, coat protein (CP), and (in some ilarvirus subgroups) a protein that suppresses RNA silencing. Here we report that, in many ilarviruses, RNA3 encodes an additional protein (termed CP-RT) as a result of ribosomal readthrough of the CP stop codon into a short downstream readthrough (RT) ORF. Using asparagus virus 2 as a model, we find that CP-RT is expressed in planta where it functions as a weak suppressor of RNA silencing. CP-RT expression is essential for persistent systemic infection in leaves and shoot apical meristem. CP-RT function is dependent on a putative zinc-finger motif within RT. Replacing the asparagus virus 2 RT with the RT of an ilarvirus from a different subgroup restored the ability to establish persistent infection. These findings open up a new avenue for research on ilarvirus silencing suppression, persistent meristem invasion and vertical transmission.

plant biology↗

bioRxiv2023

Salmonella impairs macrophage immunity through effector-independent rapid translational induction in response to membrane puncture by the SPI-1 injectisome

During bacterial infection both the host cell and its invader must divert intracellular resources to synthesise specific proteins in a timely manner. For the host, these factors may be needed for innate immune responses, including programmed cell death, and in the bacteria newly synthesized proteins may be survival factors needed to counteract host responses. Salmonella is an important food-borne bacterial pathogen that invades and multiplies within host cells. It is well established that invasion of epithelial cells is dependent upon the SPI-1 Type III injectisome, a biological needle that penetrates and secretes effectors into host cells to promote internalization. However, the importance of the SPI-1 injectisome in infection of professional phagocytes such as macrophages, which are the predominant host cell type during systemic infection, is less clear. Through time resolved parallel transcriptomic and translatomic studies of macrophage infection, we revealed that SPI-1 injectisome-dependent infection of macrophages triggers rapid translation of transcription factor mRNAs, including Early Growth Response 1 (Egr1). Despite the short half-life of EGR1 protein, its swift synthesis within the initial hour of infection is sufficient to inhibit transcription of pro-inflammatory genes and thereby restrain inflammatory responses and programmed cell death within the first hour of during early infection. This transient period of inflammatory suppression in macrophages is exploited by Salmonella to establish infection and sheds new insight on the importance of translational activation in host-pathogen dynamics during Salmonella infection.

molecular biology↗

bioRxiv2023

The structure of NAD+ consuming protein Acinetobacter baumannii TIR domain shows unique kinetics and conformations.

Toll-like and Interleukin-1/18 receptor resistance (TIR) domain-containing proteins function as important signaling and immune regulatory molecules. TIR domain-containing proteins identified in eukaryotic and prokaryotic species also exhibit NAD+ hydrolase activity in select bacteria, plants, and mammalian cells. We report the crystal structure of the Acinetobacter baumannii TIR domain protein (AbTir-TIR) with confirmed NAD+ hydrolysis and map the conformational effects of its interaction with NAD+ using HDX-MS. NAD+ results in mild decreases in deuterium uptake at the dimeric interface. In addition, AbTir-TIR exhibits EX1 kinetics indicative of large cooperative conformational changes which are slowed down upon substrate binding. Additionally, we have developed label-free imaging using 2pFLIM which shows differences in bacteria expressing native and mutant NAD+ hydrolase-inactivated AbTir-TIREA protein. Our observations are consistent with substrate-induced conformational changes reported in other TIR model systems with NAD+ hydrolase activity. These studies provide further insight into bacterial TIR protein mechanisms and their varying roles in biology.

biochemistry↗

bioRxiv2022

Severe drought events trigger long-term salt marsh dieback in the Southeastern and Gulf of Mexico USA

The frequency of salt marsh dieback events has increased over the last 25 years with unknown consequences to the resilience of the ecosystem to accelerated sea level rise (SLR). Salt marsh ecosystems impacted by sudden vegetation dieback events were previously thought to recover naturally within a few months to years. In this study, we provide evidence that approximately 14% of total marsh area has not revegetated 10-years after a dieback event in Charleston, SC. Dieback onset coincided with a severe drought in 2012, and a second dieback event occurred in 2016 after a historic flood influenced by Hurricane Joaquin in October of 2015, with unvegetated zones reaching nearly 30% of total marsh area in 2017. Most affected areas were associated with lower elevation zones in the interior of the marsh (midmarsh). During the 2013 dieback event, we estimate that unvegetated midmarsh area expanded by 300%. Grass planting was shown to be an effective restoration practice, with restored plants having greater aboveground biomass than relict sites after two years of transplanting. A positive restoration outcome indicated that the stressors that caused the initial dieback are no longer present. Despite that, many dieback areas have not recovered naturally even as they are located within the typical elevation range of a healthy vegetated marsh. A mechanistic modelling approach was used to assess the effects of vegetation dieback on salt marsh resilience to SLR. Predictions indicate that a highly productive restored marsh (2000 g m-2 y-1) would persist at a moderate SLR rate of 60 cm 100 y-1, whereas a non- restored mudflat would lose all of its elevation capital after 100 years. Thus, rapid restoration of marsh dieback is critical to avoid further degradation. Also, failure to incorporate the increasing frequency and intensity of extreme climatic events which trigger irreversible marsh diebacks underestimates salt marsh vulnerability to climate change. At an elevated SLR rate of 122 cm 100 y-1, most likely an extreme climate change scenario, even highly productive ecosystems augmented by sediment placement would not keep pace with SLR. Thus, climate change mitigation actions are also urgently needed to preserve present-day marsh ecosystems.

ecology↗

bioRxiv2019

Generation and Trapping of a Mesoderm Biased State of Human Pluripotency

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explored mesoderm lineage-bias within the human pluripotent stem cell compartment. We identified a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programs. Functionally these cells could initiate stem cell cultures and exhibited mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we could trap and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of cross-antagonistic signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.

cell biology↗

bioRxiv2019

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

Parkinsons disease (PD) is a well-known neurodegenerative disease. Recently, the role of gingipains from Porphyromonas gingivalis was implicated in Alzheimers disease. Here we present evidence of systemic inflammation, accompanied by hypercoagulation; we also show that ginipains from P. gingivalis and its LPS may foster abnormal clotting, and that ginipains are present in PD blood, and thus that ginipains action on blood may be relevant to PD pathology. Bloods from both PD and healthy blood samples were analysed using thromboelastography (TEG), confocal and electron microscopies, and for cytokine and other circulating biomarkers. We also probed PD and healthy plasma clots with a polyclonal antibody for the bacterial protease, gingipain R1, from P. gingivalis. Low concentrations of recombinant gingipain R1 were also added to purified fluorescent fibrinogen. TEG, fibrin(ogen) amyloid formation and platelet ultrastructure analysis confirmed profound hypercoagulation, while the biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. We provide evidence for the presence of the protease, gingipain R1 in PD blood, implicating inflammatory microbial cell wall products in PD.

neuroscience↗

bioRxiv2017

Common Variant Associations with Fragile X Syndrome

Fragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5x10-10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13xl0-14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75x10-5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even \"simple\" monogenetic disorders.

genetics↗