Pervasive Signal Research Articles

Redox regulation of meristem quiescence: outside/in.

Quiescence is an essential property of meristematic cells, which restrains the cell cycle while retaining the capacity to divide. This crucial process not only facilitates life-long tissue homeostasis and regenerative capacity but also provides protection against adverse environmental conditions, enabling cells to conserve the proliferative potency while minimizing DNA damage. As a survival attribute, quiescence is inherently regulated by the products of aerobic life, in particular reactive oxygen species (ROS) and the redox (reduction/oxidation) mechanisms that plant have evolved to channel these into pervasive signals. Adaptive responses allow quiescent cells to compensate for reduced oxygen tension (hypoxia) in a reversible manner, while the regulated production of the superoxide anion (O2·-) facilitates cell division and the maintenance of stem cells. Here we discuss the role of ROS and redox reactions in the control of the quiescent state in plant meristems, and how this process is integrated with cellular energy and hormone biochemistry. We consider the pathways that sense and transmit redox signals with a focus on the central significance of redox regulation in the mitochondria and nucleus, which is a major regulator of quiescence in meristems. We discuss recent studies that suggest that ROS are a critical component of the feedback loops that control stem cell identity and fate, and suggest that the ROS/hypoxia interface is an important 'outside/in' positional cue for plant cells, particularly in meristems.

Fingerprinting the geochemical signals of episodic arc activity in the Sierra Nevada batholith in space and time

Although subduction is a continuous process, arc system behavior is non-steady-state, leading to uncertainty surrounding the composite spatial and temporal evolution of transcrustal arc magma plumbing systems. This study integrates field, geochronologic, and geochemical data sets from the central Sierra Nevada arc section to investigate the extent to which spatial inheritance is recorded in arc geochemical compositions, and how these signals may be modified by dynamic arc behaviors through time, from arc-wide flare-ups, migration, and crustal thickening to regional magma focusing. Geochemical patterns across Mesozoic arc rocks characterize persistent spatial signals of inheritance, whereas geochemical trends during Cretaceous arc activity provide the temporal component of simultaneous dynamic processes. Distinct bulk-rock isotopic signals define each of the three Mesozoic magmatic flare-ups, which, during Cretaceous arc magmatism, is coupled with eastward arc migration. Additionally, Cretaceous magmatic and tectonic thickening doubled the thickness of arc crust, and magmatism was focused toward a central zone, culminating in the formation of the ∼1100 km2 Tuolumne Intrusive Complex. During magma focusing, temporal signals of magma mixing outweighed the previously pervasive signal of spatial inheritance. Distinct dynamic behaviors effectively primed the arc by the Late Cretaceous, generating transcrustal hot zones of increased magma mixing, recycling, long-term storage, and homogenization. Non-steady-state behavior in the Sierra Nevada resulted in mountain building and voluminous continental crust formation by transforming the physical, thermal, and chemical properties of the lithosphere over tens of millions of years.

Pervasive signaling

How does the increasing publicness of decisions (due, e.g., to social media) affect the total costs of social signaling distortions? While pervasive signaling may induce pervasive distortions, it may also permit people to signal while distorting each choice to a smaller degree. Ironically, for a broad class of environments, a sufficient increase in the number of signaling opportunities allows senders to “live authentically,” that is, to signal their types at arbitrarily low overall cost. This result survives when social networking technologies expand signaling opportunities and audience size in tandem, provided the returns to the latter are not too great.

Abstract 1788: Engineered destabilized AU rich elements on the 3UTR of HER2 degrades HER2, inhibits proliferation, and induces apoptosis in HER2 positive trastuzumab resistant breast cancer cells

Abstract Resistance to molecular targeted therapy is a major challenge facing breast cancer patients and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. Resistance to cancer therapies arises from many factors. One of the key factors driving resistance is oncogenes which initiate pro-growth, pro-survival and metastatic programs that enable cancers escape various therapies. In HER2+ breast cancer, the oncogene HER2 is the master driver of this tumor. Trastuzumab effectively targets HER2. While this is generally successful, some patients who have HER2+ breast cancer develop resistance to trastuzumab and there are limited treatment options for them. Moreover, for low HER2+ expressing breast cancer, there are limited treatment options for them. And in African American women who have HER2+ breast cancer, there is disparity in their treatment outcomes. We have discovered that 3’UTR of HER2 is enriched with poly U stabilizing AU rich elements (ARE). We have developed a novel technology wherein we engineered the stabilizing HER2 3’UTR ARE motifs to destabilizing motif in HER2+ and HER2+ trastuzumab resistant breast cancer cells to control HER2 transcript. We achieved complete degradation of HER2 within 4-8 days in HER2+ wildtype breast cancer cells and 9-11 days in HER2+ trastuzumab resistant breast cancer cells. We had loss of cancer cell viability by more than 90%. We also show that control of HER2 transcript downregulated HER2-dependent kinases, transcription factors, and HER2 interactome. Mechanistically, the control of HER2 transcript was achieved by destabilized ARE sequence specificity which triggered the proteins PARN, XRN1 and CNOT1 to degrade HER2 transcript and this led to induction of active caspase 3/7, reduction of cell size, and severe distortion and disruption of the cancer cell membrane leading to cell death. Taken together, we have a developed a novel approach to control HER2 transcript expression both on spatial and temporal scale. This novel approach offers applications for targeting HER2+ trastuzumab resistant breast cancer as well as other cancers resistant to HER2 targeted therapy and driven by pervasive oncogenic signals. Citation Format: Chidiebere U. Awah, Fu Dong, Fayola Levine, Leonard Ash, Yana Glemaud, Olorunseun Ogunwobi. Engineered destabilized AU rich elements on the 3UTR of HER2 degrades HER2, inhibits proliferation, and induces apoptosis in HER2 positive trastuzumab resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1788.

Identification of an allatostatin C signaling system in mollusc Aplysia

Neuropeptides, as pervasive intercellular signaling molecules in the CNS, modulate a variety of behavioral systems in both protostomes and deuterostomes. Allatostatins are neuropeptides in arthropods that inhibit the biosynthesis of juvenile hormones. Based on amino acid sequences, they are divided into three different types in arthropods: allatostatin A, allatostatin B, allatostatin C. Allatostatin C (AstC) was first isolated from Manduca sexta, and it has an important conserved feature of a disulfide bridge formed by two cysteine residues. Moreover, AstC appears to be the ortholog of mammalian somatostatin, and it has functions in common with somatostatin, such as modulating feeding behaviors. The AstC signaling system has been widely studied in arthropods, but minimally studied in molluscs. In this study, we seek to identify the AstC signaling system in the marine mollusc Aplysia californica. We cloned the AstC precursor from the cDNA of Aplysia. We predicted a 15-amino acid peptide with a disulfide bridge, i.e., AstC, using NeuroPred. We then cloned two putative allatostatin C-like receptors and through NCBI Conserved Domain Search we found that they belonged to the G protein-coupled receptor (GPCR) family. In addition, using an inositol monophosphate 1 (IP1) accumulation assay, we showed that Aplysia AstC could activate one of the putative receptors, i.e., the AstC-R, at the lowest EC50, and AstC without the disulfide bridge (AstC') activated AstC-R with the highest EC50. Moreover, four molluscan AstCs with variations of sequences from Aplysia AstC but with the disulfide bridge activated AstC-R at intermediate EC50. In summary, our successful identification of the Aplysia AstC precursor and its receptor (AstC-R) represents the first example in molluscs, and provides an important basis for further studies of the AstC signaling system in Aplysia and other molluscs.

AI-Aided Individual Emergency Detection System in Edge-Internet of Things Environments

Recently, many disasters have occurred in indoor places. In order to rescue or detect victims within disaster scenes, vital information regarding their existence and location is needed. To provide such information, some studies simply employ indoor positioning systems to identify each mobile device of victims. However, their schemes may be unreliable, since people sometimes drop their mobile devices or put them on a desk. In other words, their methods may find a mobile device, not a victim. To solve this problem, this paper proposes a novel individual monitoring system based on edge intelligence. The proposed system monitors coexisting states with a user and a smart mobile device through a user state detection mechanism, which could allow tracking through the monitoring of continuous user state switching. Then, a fine-grained localization scheme is employed to perceive the precise location of a user who is with a mobile device. Hence, the proposed system is developed as a proof-of-concept relying on off-the-shelf WiFi devices and reusing pervasive signals. The smart mobile devices of users interact with hierarchical edge computing resources to quickly and safely collect and manage sensing data of user behaviors with encryption by cipher-block chaining, and user behaviors are analyzed via the ensemble paradigm of three machine learning technologies. The proposed system shows 98.82% prevision for user activity recognition, and 96.5% accuracy for user localization accuracy is achieved.

The novel PII-interactor PirC identifies phosphoglycerate mutase as key control point of carbon storage metabolism in cyanobacteria

Nitrogen limitation imposes a major transition in the lifestyle of nondiazotrophic cyanobacteria that is controlled by a complex interplay of regulatory factors involving the pervasive signal processor PII Immediately upon nitrogen limitation, newly fixed carbon is redirected toward glycogen synthesis. How the metabolic switch for diverting fixed carbon toward the synthesis of glycogen or of cellular building blocks is operated was so far poorly understood. Here, using the nondiazotrophic cyanobacterium Synechocystis sp. PCC 6803 as model system, we identified a novel PII interactor, the product of the sll0944 gene, which we named PirC. We show that PirC binds to and inhibits the activity of 2,3-phosphoglycerate-independent phosphoglycerate mutase (PGAM), the enzyme that deviates newly fixed CO2 toward lower glycolysis. The binding of PirC to either PII or PGAM is tuned by the metabolite 2-oxoglutarate (2-OG), which accumulates upon nitrogen starvation. In these conditions, the high levels of 2-OG dissociate the PirC-PII complex to promote PirC binding to and inhibition of PGAM. Accordingly, a PirC-deficient mutant showed strongly reduced glycogen levels upon nitrogen deprivation, whereas polyhydroxybutyrate granules were overaccumulated compared to wild-type. Metabolome analysis revealed an imbalance in 3-phosphoglycerate to pyruvate levels in the pirC mutant, confirming that PirC controls the carbon flux in cyanobacteria via mutually exclusive interaction with either PII or PGAM.

Molecular Evolution of Antigen-Processing Genes in Salamanders: Do They Coevolve with MHC Class I Genes?

Proteins encoded by antigen-processing genes (APGs) prepare antigens for presentation by the major histocompatibility complex class I (MHC I) molecules. Coevolution between APGs and MHC I genes has been proposed as the ancestral gnathostome condition. The hypothesis predicts a single highly expressed MHC I gene and tight linkage between APGs and MHC I. In addition, APGs should evolve under positive selection, a consequence of the adaptive evolution in MHC I. The presence of multiple highly expressed MHC I genes in some teleosts, birds, and urodeles appears incompatible with the coevolution hypothesis. Here, we use urodele amphibians to test two key expectations derived from the coevolution hypothesis: 1) the linkage between APGs and MHC I was studied in Lissotriton newts and 2) the evidence for adaptive evolution in APGs was assessed using 42 urodele species comprising 21 genera from seven families. We demonstrated that five APGs (PSMB8, PSMB9, TAP1, TAP2, and TAPBP) are tightly linked (<0.5 cM) to MHC I. Although all APGs showed some codons under episodic positive selection, we did not find a pervasive signal of positive selection expected under the coevolution hypothesis. Gene duplications, putative gene losses, and divergent allelic lineages detected in some APGs demonstrate considerable evolutionary dynamics of APGs in salamanders. Overall, our results indicate that if coevolution between APGs and MHC I occurred in urodeles, it would be more complex than envisaged in the original formulation of the hypothesis.

A large-scale assessment of lakes reveals a pervasive signal of land use on bacterial communities.

Lakes play a pivotal role in ecological and biogeochemical processes and have been described as "sentinels" of environmental change. Assessing "lake health" across large geographic scales is critical to predict the stability of their ecosystem services and their vulnerability to anthropogenic disturbances. The LakePulse research network is tasked with the assessment of lake health across gradients of land use on a continental scale. Bacterial communities are an integral and rapidly responding component of lake ecosystems, yet large-scale responses to anthropogenic activity remain elusive. Here, we assess the ecological impact of land use on bacterial communities from over 200 lakes covering more than 660,000 km2 across Eastern Canada. In addition to community variation between ecozones, land use across Eastern Canada also appeared to alter diversity, community composition, and network structure. Specifically, increasing anthropogenic impact within the watershed lowered diversity. Likewise, community composition was significantly correlated with agriculture and urban development within a watershed. Interaction networks showed decreasing complexity and fewer keystone taxa in impacted lakes. Moreover, we identified potential indicator taxa of high or low lake water quality. Together, these findings point to detectable bacterial community changes of largely unknown consequences induced by human activity within lake watersheds.

Pacific Salmon in the Rapidly Changing Arctic: Exploring Local Knowledge and Emerging Fisheries in Utqiaġvik and Nuiqsut, Alaska

One of the most pervasive signals of global climate change is altered patterns of distribution with trends towards poleward shifts of species. While habitat loss and destruction has severed connections between people and salmon in many locales, salmon fisheries in the high Arctic are just beginning to develop. To explore these emergent connections, we gathered local knowledge about Pacific salmon and emerging subsistence salmon fisheries in the Beaufort Sea region through ethnographic research in Utqiaġvik (formerly Barrow) and Nuiqsut, Alaska. Between 2010 and 2013, we interviewed 41 active fishermen and Elders who generally agreed that harvests of Pacific salmon species have been increasing in recent years, beginning in the 1990s and early 2000s. About 46% of active fishermen and Elders who discussed salmon abundance perceived an increasing trend over time. Another 43% characterized salmon abundance as cyclical or perceived no directional trend over time. The remaining fishermen (all from Nuiqsut) expressed their perception of decreasing salmon and fish abundance overall related to oil and gas development impacts to their local lands and waters. Given these mixed perceptions and harvests being an imperfect proxy for abundance, it remains unclear whether salmon populations are expanding in Arctic river systems. However, research participants have identified new stream systems not currently documented in the scientific literature where salmon are present and thought to be spawning. In both communities, we found that many fishermen and Elders often do not differentiate Pacific salmon species. Fishermen in both communities are developing new knowledge of salmon and increasing their use of salmon as a subsistence resource, yet uncertainties in the current data and local knowledge combine to generate equivocal evidence that salmon abundance is increasing. This lack of a clear increase in salmon abundance provides nuance to a simple story that warming has led to the increases of salmon in the Arctic. Despite the uncertainty regarding abundance, it is clear we are witnessing an emergence of new salmon fisheries in the high Arctic, perceived to be one among a suite of environmental and social changes currently being experienced in this region.

Against the odds? – A study of educational attainment and labour market position of the second-generation ethnic minority members in the UK

Much research in the UK has shown a close relationship between family position and educational attainment. Yet, this association seems to apply to whites rather than to children from ethnic minority backgrounds who are usually found to outperform whites in spite of their poorer family situation. The classical theories do not give an adequate account of this apparent mismatch as they were designed for the general population. I propose a thesis of ‘reinvigorated ambition’ to try to explain the second-generation drive for success. Drawing data from the UK Household Longitudinal Study, I show that multiple disadvantages faced by ethnic minorities in the labour market give pervasive signals to the second generation that they have to aim higher and work harder in order not to fall too low in their life trajectory. The educational success of children from ethnic minority heritages can thus be seen as a determined effort to shield off cumulative discrimination in the labour market and in wider society.

Functional characterization of the upstream components of the Hog1-like kinase cascade in hyperosmotic and carbon sensing in Trichoderma reesei

BackgroundTrichoderma reesei holds a high capacity for protein secretion and represents the most important cellulase producer in industry. However, the external signal sensing and intracellular signal transduction during cellulose induction remain unclear. As one of the most pervasive signal transduction pathways in all eukaryotic species, the mitogen-activated protein kinase (MAPK) pathway and its upstream sensing and signaling components are involved in various physiological processes including stress and nutrient sensing. Particularly, the Hog1-type MAPK Tmk3 has been reported to be involved in the cellulase production in T. reesei.ResultsHere we established the physiological role of two upstream regulatory branches, the Sho1 branch and the Sln1 branch, of the Hog1-type Tmk3 pathway in T. reesei. Deletion of Trste20 of the Sho1 branch or repression of Trypd1 of the Sln1 branch reduced the resistance to high salt stress, whereas TrSho1 showed an opposing effect to that of TrSte20 and the identified TrSln1 seemed to be dispensable in the osmotic regulation. The Sho1 and Sln1 branches also participated in the cell wall integrity maintenance and other stress responses (i.e. oxidative and thermo stresses). Notably, TrSho1 and TrSte20 of the Sho1 branch and TrYpd1 of the Sln1 branch were shown to be differentially involved in the cellulase production of T. reesei. Repression of Trypd1 hardly affected cellulase induction, whereas overexpression of Trypd1 resulted in the reduced production of cellulases. Contrary to the case of Trypd1, repression of Trsho1 or deletion of Trste20 significantly reduced the transcription of cellulase genes.ConclusionsTrSho1 and TrSte20 of the Sho1 branch and TrYpd1 of the Sln1 branch are all involved in general stress responses including hyperosmotic regulation and cell wall integrity maintenance. Moreover, our study revealed that the Sho1 and Sln1 osmosensing pathways are differentially involved in the regulation of cellulase production in T. reesei. The Sho1 branch positively regulated the production of cellulases and the transcription of cellulase genes while TrYpd1 of the Sln1 branch negatively controlled the cellulase production, supporting the crosstalks of osmosensing and nutrient sensing.

The brain as a "hyper-network": the key role of neural networks as main producers of the integrated brain actions especially via the "broadcasted" neuroconnectomics.

Investigations of brain complex integrative actions should consider beside neural networks, glial, extracellular molecular, and fluid channels networks. The present paper proposes that all these networks are assembled into the brain hyper-network that has as fundamental components, the tetra-partite synapses, formed by neural, glial, and extracellular molecular networks. Furthermore, peri-synaptic astrocytic processes by modulating the perviousness of extracellular fluid channels control the signals impinging on the tetra-partite synapses. It has also been surmised that global signalling via astrocytes networks and highly pervasive signals, such as electromagnetic fields (EMFs), allow the appropriate integration of the various networks especially at crucial nodes level, the tetra-partite synapses. As a matter of fact, it has been shown that astrocytes can form gap-junction-coupled syncytia allowing intercellular communication characterised by a rapid and possibly long-distance transfer of signals. As far as the EMFs are concerned, the concept of broadcasted neuroconnectomics (BNC) has been introduced to describe highly pervasive signals involved in resetting the information handling of brain networks at various miniaturisation levels. In other words, BNC creates, thanks to the EMFs, generated especially by neurons, different assemblages among the various networks forming the brain hyper-network. Thus, it is surmised that neuronal networks are the "core components" of the brain hyper-network that has as special "nodes" the multi-facet tetra-partite synapses. Furthermore, it is suggested that investigations on the functional plasticity of multi-partite synapses in response to BNC can be the background for a new understanding and perhaps a new modelling of brain morpho-functional organisation and integrative actions.

Phenotypic diversity and temporal variability in a bacterial signaling network revealed by single-cell FRET.

We present in vivo single-cell FRET measurements in the Escherichia coli chemotaxis system that reveal pervasive signaling variability, both across cells in isogenic populations and within individual cells over time. We quantify cell-to-cell variability of adaptation, ligand response, as well as steady-state output level, and analyze the role of network design in shaping this diversity from gene expression noise. In the absence of changes in gene expression, we find that single cells demonstrate strong temporal fluctuations. We provide evidence that such signaling noise can arise from at least two sources: (i) stochastic activities of adaptation enzymes, and (ii) receptor-kinase dynamics in the absence of adaptation. We demonstrate that under certain conditions, (ii) can generate giant fluctuations that drive signaling activity of the entire cell into a stochastic two-state switching regime. Our findings underscore the importance of molecular noise, arising not only in gene expression but also in protein networks.

When and Why are Principal Component Scores a Good Tool for Visualizing High‐dimensional Data?

AbstractPrincipal component analysis is a popular dimension reduction technique often used to visualize high‐dimensional data structures. In genomics, this can involve millions of variables, but only tens to hundreds of observations. Theoretically, such extreme high dimensionality will cause biased or inconsistent eigenvector estimates, but in practice, the principal component scores are used for visualization with great success. In this paper, we explore when and why the classical principal component scores can be used to visualize structures in high‐dimensional data, even when there are few observations compared with the number of variables. Our argument is twofold: First, we argue that eigenvectors related to pervasive signals will have eigenvalues scaling linearly with the number of variables. Second, we prove that for linearly increasing eigenvalues, the sample component scores will be scaled and rotated versions of the population scores, asymptotically. Thus, the visual information of the sample scores will be unchanged, even though the sample eigenvectors are biased. In the case of pervasive signals, the principal component scores can be used to visualize the population structures, even in extreme high‐dimensional situations.

A Simultaneous Extraction of Context and Community from pervasive signals using nested Dirichlet process

Understanding user contexts and group structures plays a central role in pervasive computing. These contexts and community structures are complex to mine from data collected in the wild due to the unprecedented growth of data, noise, uncertainties and complexities. Typical existing approaches would first extract the latent patterns to explain human dynamics or behaviors and then use them as a way to consistently formulate numerical representations for community detection, often via a clustering method. While being able to capture high-order and complex representations, these two steps are performed separately. More importantly, they face a fundamental difficulty in determining the correct number of latent patterns and communities. This paper presents an approach that seamlessly addresses these challenges to simultaneously discover latent patterns and communities in a unified Bayesian nonparametric framework. Our Simultaneous Extraction of Context and Community (SECC) model roots in the nested Dirichlet process theory which allows a nested structure to be built to summarize data at multiple levels. We demonstrate our framework on five datasets where the advantages of the proposed approach are validated.

Genomic Patterns of Positive Selection at the Origin of Rust Fungi.

Understanding the origin and evolution of pathogenicity and biotrophic life-style of rust fungi has remained a conundrum for decades. Research on the molecular mechanisms responsible for rust fungi evolution has been hampered by their biotrophic life-style until the sequencing of some rust fungi genomes. With the availability of multiple whole genomes and EST data for this group, it is now possible to employ genome-wide surveys and investigate how natural selection shaped their evolution. In this work, we employed a phylogenomics approach to search for positive selection and genes undergoing accelerated evolution at the origin of rust fungi on an assembly of single copy genes conserved across a broad range of basidiomycetes. Up to 985 genes were screened for positive selection on the phylogenetic branch leading to rusts, revealing a pervasive signal of positive selection throughout the data set with the proportion of positively selected genes ranging between 19.6–33.3%. Additionally, 30 genes were found to be under accelerated evolution at the origin of rust fungi, probably due to a mixture of positive selection and relaxation of purifying selection. Functional annotation of the positively selected genes revealed an enrichment in genes involved in the biosynthesis of secondary metabolites and several metabolism and transporter classes.

Targeted transgenesis identifies Gαs as the bottleneck in β2-adrenergic receptor cell signaling and physiological function in airway smooth muscle.

G protein-coupled receptors are the most pervasive signaling superfamily in the body and act as receptors to endogenous agonists and drugs. For β-agonist-mediated bronchodilation, the receptor-G protein-effector network consists of the β2-adrenergic receptor (β2AR), Gs, and adenylyl cyclase, expressed on airway smooth muscle (ASM). Using ASM-targeted transgenesis, we previously explored which of these three early signaling elements represents a limiting factor, or bottleneck, in transmission of the signal from agonist binding to ASM relaxation. Here we overexpressed Gαs in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Gαs expression. Contraction of ASM from acetylcholine was not affected in Gαs transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from Gαs-transgenic mice was enhanced compared with ASM from nontransgenic littermates. Agonist-promoted inhibition of platelet-derived growth factor-stimulated ASM proliferation was also enhanced in Gαs mouse ASM. The enhanced maximal β-agonist response was of similar magnitude for relaxation, cAMP production, and growth inhibition. Taken together, it appears that a limiting factor in β-agonist responsiveness in ASM is the expression level of Gαs. Gene therapy or pharmacological means of increasing Gαs (or its coupling efficiency to β2AR) thus represent an interface for development of novel therapeutic agents for improvement of β-agonist therapy.

Dimerization-based control of cooperativity.

Cooperativity of ligand-receptor binding influences the input-output behavior of a biochemical system and thus is an important determinant of its physiological function. Canonically, such cooperativity is understood in terms of ligand-receptor binding affinity, where an initial binding event changes the affinity for subsequent binding events. Here, we demonstrate that dimerization-a simple yet pervasive signaling motif across biology-can have significant control over cooperativity and even dominate over the canonical mechanism. Through an exhaustive parameter sensitivity analysis of a general kinetic model for signal-mediated dimerization, we show that quantitative modulation of dimerization processes can reinforce, eliminate, and even reverse cooperativity imposed by the canonical allosteric ligand-receptor binding affinity mechanism. The favored accumulation of stoichiometrically asymmetric dimers (those with ligand-receptor stoichiometry of 1 : 2) is a major determinant of dimerization-based cooperativity control. However, simulations demonstrate that favoring accumulation of such stoichiometrically asymmetric dimers can either increase or decrease cooperativity, and thus the quantitative relationship between stoichiometrically asymmetric dimers and cooperativity is highly dependent on the parameter values of the particular system of interest. These results suggest that the dimerization motif provides a novel mechanism for both generating and quantitatively tuning cooperativity that, due to the ubiquity of dimerization motifs in biochemical systems, may play a major role in a host of biological functions. Thus, the canonical, allosteric view of cooperativity is incomplete without considering dimerization effects, which is of particular importance as dimerization is often a necessary feature of the allosteric mechanism.

Accessing Hunter-Gatherer site structures using Fourier transform infrared spectroscopy: applications at a Taltheilei settlement in the Canadian Sub-Arctic

The results of Fourier transform infrared spectroscopy on soils and caribou bone from a Taltheilei culture settlement in northern Canada contribute to developing micro-archaeological approaches suitable for locating and characterizing hearth and midden features on hunter-gatherer sites. A weak yet pervasive signal for montgomeryite was developed from the diagenesis of dispersed ash and caribou processing residues. Disordered calcite, carbonate hydroxylapatite, charcoal, and burned bone in two pit-house hearth deposits indicate that both wood and bone were used for fuel. Crystallinity indices and carbonate/phosphate ratios for bone indicate high intensity burning. These data, in tandem with the presence of semi-subterranean dwellings, demonstrate that this particular tundra-based encampment was occupied during cold seasons, a type of settlement behaviour previously unrecognized in the Taltheilei archaeological record. Our results confirm that Fourier transform infrared spectroscopy is an accessible, rapid, and cost effective means of discovering micro-archaeological evidence valuable for reconstructing hunter-gatherer site structures.