Biology subjects

Miller, R.

Publications and source records attributed to Miller, R..

66 records · Page 4Linked to original sources

bioRxiv2020

Understanding signaling and metabolic paths using semantified and harmonized information about biological interactions

BackgroundTo grasp the complexity of biological processes, the biological knowledge is often translated into schematic diagrams of biological pathways, such as signalling and metabolic pathways. These pathway diagrams describe relevant connections between biological entities and incorporate domain knowledge in a visual format that is easier for humans to interpret. It has already been established that these diagrams can be represented in machine readable formats, as done in KEGG, Reactome, and WikiPathways. However, while humans are good at interpreting the message of the creator of such a diagram, algorithms struggle when the diversity in drawing approaches increases. WikiPathways supports multiple drawing styles, and therefore needs to harmonize this to offer semantically enriched access via the Resource Description Framework format. Particularly challenging in the normalization of diagrams are the interactions between the biological entities, so that we can glean information about the connectivity of the entities represented. These interactions include information about the type of interaction (metabolic conversion, inhibition, etc.), the direction, and the participants. Availability of the interactions in a semantic and harmonized format enables searching the full network of biological interactions and integration with the linked data cloud. ResultsWe here study how the graphically modelled biological knowledge in diagrams can be semantified and harmonized efficiently, and exemplify how the resulting data can be used to programmatically answer biological questions. We find that we can translate graphically modelled biological knowledge to a sufficient degree into a semantic model of biological knowledge and discuss some of the current limitations. Furthermore, we show how this interaction knowledge base can be used to answer specific biological questions. ConclusionThis paper demonstrates that most of the graphical biological knowledge from WikiPathways is modelled in the semantic layer of WikiPathways with the semantic information intact and connectivity information preserved. The usability of the WikiPathways pathway and connectivity information has shown to be useful and has been integrated into other platforms. Being able to evaluate how biological elements affect each other is useful and allows, for example, the identification of up or downstream targets that will have a similar effect when modified.

bioinformatics↗

bioRxiv2020

Optimizing nucleic acid extraction and transcriptome evaluation from low-input, fixed clinical samples

Tumor biopsies are commonly formalin-fixed and paraffin-embedded (FFPE) for long-term and efficient storage. However, FFPE preservation can greatly compromise the quality of samples, the extraction of nucleic acids, and feasibility of downstream studies, including RNA sequencing. These challenges are especially evident in the studies of clinical trial samples, where the sizes of biopsies often limit the amount of material available for study. Here, we evaluate two nucleic acid extraction kits (Covaris truXTRAC FFPE tNA Plus, QIAGEN miRNeasy FFPE) and three hybridized-capture-based RNA sequencing library preparations (Agilent SureSelect XT RNA Direct, Agilent SureSelect XT HS, and Illumina TruSeq RNA Exome) to evaluate the impact of these sample processing steps on transcriptome evaluation in a melanoma biopsy procured in a clinical setting and preserved by FFPE. While there exist many options for extraction and library preparation that are appropriate for RNA sequencing from FFPE samples, we observed that combinations of experimental approaches may have subtle impacts on downstream analysis, including gene expression quantification and fusion detection.

genomics↗

bioRxiv2020

Genome-wide identification and characterization of Solanum tuberosum BiP genes reveals the role of the promoter architecture in BiP gene diversity

The endoplasmic reticulum (ER) immunoglobulin binding proteins (BiPs) are molecular chaperones involved in normal protein maturation and refolding malformed proteins through the unfolded protein response (UPR). Plants BiPs belong to a multi-gene family contributing to development, immunity, and responses to environmental stresses. This study identified three BiP homologues in the Solanum tuberosum (potato) genome using phylogenetic, amino acid sequence, 3-D protein modeling and gene structure analysis. These analyses revealed that StBiP1 and StBiP2 grouped with AtBiP2, whereas StBiP3 grouped with AtBiP3. While the protein sequences and folding structures are highly similar, these StBiPs are distinguishable by their expression patterns in different tissues and in response to environmental stressors such as treatment with heat, chemicals, or virus elicitors of UPR. Ab initio promoter analysis revealed that potato and Arabidopsis BiP1 and BiP2 promoters were highly enriched with cis regulatory elements (CREs) linked to developmental processes, whereas BiP3 promoters were enriched with stress-related CREs. The frequency and linear distribution of these CREs produced two phylogenetic branches that further resolve the groups identified through gene phylogeny and exon/intron phase analysis. These data reveal that the CRE architecture of BiP promoters potentially define their spatio -temporal expression patterns under developmental and stress related cues.

plant biology↗

bioRxiv2019

Optimal spatial prioritization of control resources for elimination of invasive species under demographic uncertainty

Populations of invasive species often spread heterogeneously across a landscape, consisting of local populations that cluster in space but are connected by dispersal. A fundamental dilemma for invasive species control is how to optimally allocate limited fiscal resources across local populations. Theoretical work based on perfect knowledge of demographic connectivity suggests that targeting local populations from which migrants originate (sources) can be optimal. However, demographic processes such as abundance and dispersal can be highly uncertain, and the relationship between local population density and damage costs (damage function) is rarely known. We used a metapopulation model to understand how observational uncertainty in abundance and connectivity, and imperfect knowledge of the damage function, affect return on investment (ROI) for optimal control strategies. Budget, observational uncertainty, and the damage function had strong effects on the optimal resource allocation strategy. Uncertainty in dispersal probability was the least important determinant of ROI. The damage function determined which resource prioritization strategy was optimal when connectivity was symmetric but not when it was asymmetric. When connectivity was asymmetric, prioritizing source populations had a higher ROI than allocating effort equally across local populations, regardless of the damage function, but uncertainty in connectivity structure and abundance reduced ROI of the optimal prioritization strategy by 57% on average depending on the control budget. With low budgets (monthly removal rate of 6.7% of population), there was little advantage to prioritizing resources, especially when connectivity was high or symmetric, and observational uncertainty had only minor effects on ROI. Allotting funding for improved monitoring appeared to be most important when budgets were moderate (monthly removal of 13-20% of the population). Our result showed that multiple sources of observational uncertainty should be considered concurrently for optimizing ROI. Accurate estimates of connectivity direction and abundance were more important than accurate estimates of dispersal rates. Developing cost-effective surveillance methods to reduce observational uncertainties, and quantitative frameworks for determining how resources should be spatially apportioned to multiple monitoring and control activities are important and challenging future directions for optimizing ROI for invasive species control programs.

ecology↗

bioRxiv2019

Modulation of longevity by diet, and youthful body weight, but not by weight gain after maturity

Diet and environment profoundly modulate lifespan. We measured longevity as a function of diet and weight gain across a genetically diverse family of mice. We followed 1348 females from two parental strains--C57BL/6J and DBA/2J--and 146 cohorts of BXD isogenic progeny strains (n = 73) across their lifespan on a low fat chow diet (CD, 18% calories from fat) and on a high fat diet (HFD, 60% calories from fat). On average, HFD shortens lifespan by 85 days or 12%, roughly equivalent to an 8-10 year decrease in humans. However, strain variation in the response of diet on longevity is remarkably high, ranging from a longevity loss of 54% in BXD65 to a gain of 37% in BXD8. Baseline weights and early weight gain are both associated with a mean decrease in longevity of [~]4 days/g. By 500 days-of-age, cases fed HFD gained four times as much weight as control on average. However, strain-specific variation was substantial, thus weight gain did not correlate well with lifespan. In summary, high fat had a strong negative effect on longevity, but genetic interactions effects were even stronger. This highlights the unequivocal importance of genetic differences in making dietary recommendations.

genetics↗

bioRxiv2019

Decision-making flexibility in New Caledonian crows, young children and adult humans in a multi-dimensional tool-use task

The ability to make profitable decisions in natural foraging contexts may be influenced by an additional requirement of tool-use, due to increased levels of relational complexity and additional work-effort imposed by tool-use, compared with simply choosing between an immediate and delayed food item. We examined the flexibility for making the most profitable decisions in a multi-dimensional tool-use task, involving different apparatuses, tools and rewards of varying quality, in 3-5-year-old children, adult humans and tool-making New Caledonian crows (Corvus moneduloides). We also compared our results to previous studies on habitually tool-making orangutans (Pongo abelii) and non-tool-making Goffins cockatoos (Cacatua goffiniana). Adult humans, cockatoos and crows, though not children and orangutans, did not select a tool when it was not necessary, which was the more profitable choice in this situation. Adult humans, orangutans and cockatoos, though not crows and children, were able to refrain from selecting non-functional tools. By contrast, the birds, though not primates tested, struggled to attend to multiple variables - where two apparatuses, two tools and two reward qualities were presented simultaneously - without extended experience. These findings indicate: (1) in a similar manner to humans and orangutans, New Caledonian crows and Goffins cockatoos can flexibly make profitable decisions in some decision-making tool-use tasks, though the birds may struggle when tasks become more complex; (2) children and orangutans may have a bias to use tools in situations where adults and other tool-making species do not.

animal behavior and cognition↗

bioRxiv2019

Whole Brain Polarity Regime Dynamics are Significantly Disrupted in Schizophrenia and Correlate Strongly with Network Connectivity Measures

From a large clinical blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) study, we report several interrelated findings involving transient supra-network brainwide states characterized by a saturation phenomenon we are referring to as "polarization." These are whole-brain states in which the voxelwise-normalized BOLD (vnBOLD) activation of a large proportion of voxels is simultaneously either very high or very low. The presence of such states during a resting-state fMRI (rs-fMRI) scan is significantly anti-correlated with diagnosed schizophrenia, significantly anti-correlated with connectivity between subcortical networks and auditory, visual and sensorimotor networks and also significantly anti-correlated with contemporaneous occupancy of transient functional network connectivity states featuring broad disconnectivity or strong inhibitory connections between the default mode and other networks. Conversely, the presence of highly polarized vn-BOLD states is significantly correlated with connectivity strength between auditory, visual and sensorimotor networks and with contemporaneous occupancy of transient whole-brain patterns of strongly modularized network connectivity and diffuse hyperconnectivity. Despite their consistency with well-documented effects of schizophrenia on static and time-varying functional network connectivity, the observed relationships between polarization and network connectivity are with very few exceptions unmediated by schizophrenia diagnosis. We also find that the spatial distribution of voxels most likely to contribute to the highly polarized states (polarity participation maps (PPMs)) differs with a high degree of statistical significance between schizophrenia patients and healthy controls. Finally, we report evidence suggesting the process by which the most polarized states are achieved, i.e. the ways that strongly polarized voxel regions extend, merge and recede also differs significantly between patient and control populations. Many differences observed between patients and controls are echoed within the patient population itself in the effect patterns of positive symptomology (e.g. hallucinations, delusions, grandiosity and other positive symptoms of schizophrenia). Our findings highlight a particular whole-brain spatiotemporal BOLD activation phenomenon that differs markedly between healthy subjects and schizophrenia patients, one that also strongly informs time-resolved network connectivity patterns that are associated with this serious clinical disorder.

neuroscience↗

bioRxiv2018

MiR-146a wild-type 3’ sequence identity is dispensable for proper innate immune function in vivo

The prevailing model of microRNA function is that the \"seed\" region (nucleotides 2-8) is typically sufficient to mediate target recognition and repression. However, numerous recent studies have challenged this model, either by demonstrating extensive 3 pairing between physically defined miRNA-mRNA pairs or by showing in C. elegans that disrupted 3 pairing can result in impaired function in vivo. To test the importance of miRNA 3 pairing in a mammalian system in vivo, we engineered a mutant murine mir-146a allele in which the 5 half of the mature microRNA retains its wild-type sequence, but the 3 half has been altered to be anti-complementary. Mice homozygous or hemizygous for this mutant allele are phenotypically indistinguishable from wild-type controls and do not recapitulate any of the immunopathology previously described for mir-146a-null mice. Our results indicate that 3 pairing is dispensable for the established myeloid function of this key mammalian microRNA.\n\nSummary Blurb3 sequence identity is dispensable for the established function of a mammalian miRNA in vivo.

genetics↗

bioRxiv2018

Cystinosin regulates kidney inflammation through its interaction with galectin-3

Inflammation is implicated in the pathogenesis of many disorders. Here, we show that cystinosin, protein defective in the lysosomal storage disorder cystinosis, is a critical regulator of galectin-3 during inflammation. Cystinosis is a lysosomal storage disorder and despite ubiquitous expression of cystinosin, kidney is the primary organ to be impacted by the disease. Here, we show that cystinosin interacts with galectin-3 and enhances its lysosomal localization and degradation. Galectin-3 is also found overexpressed in the kidney of the mouse model of cystinosis, Ctns-/-mice. Absence of galectin-3 in Ctns-/- mice led to a better renal function and structure, and decreased macrophage/monocyte infiltration in the kidney. Finally, galectin-3 interacts with a protein implicated in the recruitment of monocytes and macrophages during inflammation, Monocyte Chemoattractant Protein-1 (MCP1), that was found increased in the serum of Ctns-/- mice. These findings highlight a new role of cystinosin and galectin-3 interaction in inflammation, providing a mechanistic explanation for kidney disease pathogenesis in cystinosis, which may lead to the identification of new drug targets to delay its progression.

molecular biology↗

bioRxiv2017

An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

Pain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374 A). Further cleavage by MMPs (N341-342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type but not Tlr2 null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

neuroscience↗

bioRxiv2017

In vivo calcium imaging visualizes peripheral neuron sensitization in murine osteoarthritis

ObjectiveThe purpose of this study was to develop a method for analyzing sensory neuron responses to mechanical stimuli in vivo, and to evaluate whether these neuronal responses change after destabilization of the medial meniscus (DMM).\n\nMethodsDMM or sham surgery was performed in 10-week old male C57BL/6 wild-type or Pirt-GCaMP3+/- mice. All experiments were performed eight weeks after surgery. Knee and hind paw hyperalgesia were assessed in wild-type mice. The retrograde label DiI was injected into the ipsilateral knee to quantify the number of knee-innervating neurons in the L4 dorsal root ganglion (DRG) in wild-type mice. In vivo calcium imaging was performed on the ipsilateral L4 DRG of Pirt-GCaMP3+/- mice as mechanical stimuli (paw pinch, knee pinch, knee twist) were applied to the ipsilateral hind limb.\n\nResultsEight weeks after surgery, DMM mice had more hyperalgesia in the knee and hind paw compared to sham mice. Intra-articular injection of DiI labeled similar numbers of neurons in the L4 DRG of sham and DMM mice. Increased numbers of sensory neurons responded to all three mechanical stimuli in DMM mice, as assessed by in vivo calcium imaging. The majority of responses in sham and DMM mice were in small-to-medium-sized neurons, consistent with the size of nociceptors. The magnitude of responses was similar between sham and DMM mice.\n\nConclusionsWe demonstrated that increased numbers of small-to-medium sized DRG neurons respond to mechanical stimuli 8 weeks after DMM surgery, suggesting that nociceptors have become sensitized by lowering the response threshold.

neuroscience↗

bioRxiv2016

Summary of muscle parameters for Hill-based muscle modeling in the human lower limb

A summary is presented of five mechanical parameters from human lower limb skeletal muscles critical for Hill-based muscle modeling: the optimal fiber length, the fiber pennation angle, the physiological cross-sectional area (PCSA), the unloaded tendon length, and the fast-twitch fiber fraction. The data presented are drawn from a total of 29 publications including human cadaver studies, in vivo imaging studies of live humans, musculoskeletal modeling studies, and combinations of these methods. Where possible, parameter values were adjusted from the referenced data to present them with consistent definitions (normalization of measured fiber lengths to optimal sarcomere length, and calculation of PCSA as the ratio of fiber volume to fiber length). It is seen that within a specific muscle, optimal fiber lengths are fairly consistent between studies, pennation angles and PCSAs vary widely between studies, and data for unloaded tendon length are comparatively sparse. Few studies have reported fiber type fractions for a large number of muscles. Guidelines for implementing these parameter values in muscle modeling and musculoskeletal modeling are suggested.\n\nUpdate HistoryO_LIDecember 2, 2016: original submission\nC_LIO_LIDecember 3, 2016: discussion on maximum isometric force and specific tension added\nC_LIO_LIDecember 6, 2016: minor edits for typos, clarity, and missing references\nC_LIO_LIDecember 7, 2016: Tirrell et al. (2012) study added\nC_LI

bioengineering↗