Cellular automata modelling of slime mould actin network signalling

© 2016, The Author(s). Actin is a cytoskeletal protein which forms dense, highly interconnected networks within eukaryotic cells. A growing body of evidence suggests that actin-mediated intra- and extracellular signalling is instrumental in facilitating organism-level emergent behaviour patterns which, crucially, may be characterised as natural expressions of computation. We use excitable cellular automata modelling to simulate signal transmission through cell arrays whose topology was extracted from images of Watershed transformation-derived actin network reconstructions; the actin networks sampled were from laboratory experimental observations of a model organism, slime mould Physarum polycephalum. Our results indicate that actin networks support directional transmission of generalised energetic phenomena, the amplification and trans-network speed of which of which is proportional to network density (whose primary determinant is the anatomical location of the network sampled). Furthermore, this model also suggests the ability of such networks for supporting signal-signal interactions which may be characterised as Boolean logical operations, thus indicating that a cell’s actin network may function as a nanoscale data transmission and processing network. We conclude by discussing the role of the cytoskeleton in facilitating intracellular computing, how computation can be implemented in such a network and practical considerations for designing ‘useful’ actin circuitry

Gene expression differences in relation to age and social environment in queen and worker bumble bees

Eusocial insects provide special insights into the genetic pathways influencing aging because of their long-lived queens and flexible aging schedules. Using qRT-PCR in the primitively eusocial bumble bee Bombus terrestris (Linnaeus), we investigated expression levels of four candidate genes associated with taxonomically widespread age-related pathways (coenzyme Q biosynthesis protein 7, COQ7; DNA methyltransferase 3, Dnmt3; foraging, for; and vitellogenin, vg). In Experiment 1, we tested how expression changes with queen relative age and productivity. We found a significant age-related increase in COQ7 expression in queen ovary. In brain, all four genes showed higher expression with increasing female (queen plus worker) production, with this relationship strengthening as queen age increased, suggesting a link with the positive association of fecundity and longevity found in eusocial insect queens. In Experiment 2, we tested effects of relative age and social environment (worker removal) in foundress queens and effects of age and reproductive status in workers. In this experiment, workerless queens showed significantly higher for expression in brain, as predicted if downregulation of for is associated with the cessation of foraging by foundress queens following worker emergence. Workers showed a significant age-related increase in Dnmt3 expression in fat body, suggesting a novel association between aging and methylation in B. terrestris. Ovary activation was associated with significantly higher vg expression in fat body and, in younger workers, in brain, consistent with vitellogenin's ancestral role in regulating egg production. Overall, our findings reveal a mixture of novel and conserved features in age-related genetic pathways under primitive eusociality

Strengthening adult mosquito surveillance in Africa for disease control: Learning from the present

Mosquito surveillance is essential to successfully control and eliminate mosquito-borne diseases. Yet, it is often done by numerous organizations with little collaboration, incomplete understanding of existing gaps, and limited long-term vision. There is a clear disconnect between entomological and epidemiological indices, with entomological data informing control efforts inadequately. Here we discuss current mosquito surveillance practises across the heterogenous disease landscape in Africa. We advocate for the development of mosquito surveillance strategic plans to increase the impact and functionality of mosquito surveillance. We urge for a proactive approach to set up centralized mosquito data systems under custodian of national governments, focus on epidemiologically relevant mosquito data and increase robustness of mosquito surveillance using a more spatially explicit sampling design

Point-of-Care Testing for Toxoplasma Gondii IgG/IgM Using Toxoplasma ICT IgG-IgM Test with Sera from the United States and Implications for Developing Countries

Background Congenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved. Methods We tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed. Results We found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM-positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients. Conclusions Our work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal-fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries

Factors related to human-vector contact that modify the likelihood of malaria transmission during a contained Plasmodium falciparum outbreak in Praia, Cabo Verde

Background: Determining the reproductive rate and how it varies over time and space (RT) provides important insight to understand transmission of a given disease and inform optimal strategies for controlling or eliminating it. Estimating RT for malaria is difficult partly due to the widespread use of interventions and immunity to disease masking incident infections. A malaria outbreak in Praia, Cabo Verde in 2017 provided a unique opportunity to estimate RT directly, providing a proxy for the intensity of vector-human contact and measure the impact of vector control measures. Methods: Out of 442 confirmed malaria cases reported in 2017 in Praia, 321 (73%) were geolocated and informed this analysis. RT was calculated using the joint likelihood of transmission between two cases, based on the time (serial interval) and physical distance (spatial interval) between them. Log-linear regression was used to estimate factors associated with changes in RT, including the impact of vector control interventions. A geostatistical model was developed to highlight areas receptive to transmission where vector control activities could be focused in future to prevent or interrupt transmission. Results: The RT from individual cases ranged between 0 and 11 with a median serial- and spatial-interval of 34 days [interquartile range (IQR): 17–52] and 1,347 m (IQR: 832–1,985 m), respectively. The number of households receiving indoor residual spraying (IRS) 4 weeks prior was associated with a reduction in RT by 0.84 [95% confidence interval (CI) 0.80–0.89; p-value <0.001] in the peak-and post-epidemic compared to the pre-epidemic period. Conclusions: Identifying the effect of reduced human-vector contact through IRS is essential to determining optimal intervention strategies that modify the likelihood of malaria transmission and can inform optimal intervention strategies to accelerate time to elimination. The distance within which two cases are plausibly linked is important for the potential scale of any reactive interventions as well as classifying infections as imported or introduced and confirming malaria elimination

Rho GTPase Cdc42 Is a Direct Interacting Partner of Adenomatous Polyposis Coli Protein and Can Alter Its Cellular Localization

Adenomatous Polyposis Coli (APC) is a tumor suppressor gene product involved in colon cancer. APC is a large multidomain molecule of 2843 amino acid residues and connects cell-cell adhesion, the F-actin/microtubule cytoskeleton and the nucleus. Here we show that Cdc42 interacts directly with the first three armadillo repeats of APC by yeast two-hybrid screens. We confirm the Cdc42-APC interaction using pulldown assays in vitro and FRET assays in vivo. Interestingly, Cdc42 interacts with APC at leading edge sites where F-actin is enriched. In contrast, Cdc42 interacts with the truncated mutant APC1–1638 in cellular puncta associated with the golgi-lysozome pathway in transfected CHO cells. In HCT116 and SW480 cells, Cdc42 induces the relocalization of endogenous APC and the mutant APC1–1338 to the plasma membrane and cellular puncta, respectively. Taken together, these data indicate that the Cdc42-APC interaction induces localization of both APC and mutant APC and may thus play a direct role in the functions of these proteins

Human Immunodeficiency Virus type 1 Endocytic Trafficking Through Macrophage Bridging Conduits Facilitates Spread of Infection

Bridging conduits (BC) sustain communication and homeostasis between distant tethered cells. These are also exploited commonly for direct cell-to-cell transfer of microbial agents. Conduits efficiently spread infection, effectively, at speeds faster than fluid phase exchange while shielding the microbe against otherwise effective humoral immunity. Our laboratory has sought to uncover the mechanism(s) for these events for human immunodeficiency virus type one (HIV-1) infection. Indeed, in our prior works HIV-1 Env and Gag antigen and fluorescent virus tracking were shown sequestered into endoplasmic reticulum-Golgi organelles but the outcomes for spreading viral infection remained poorly defined. Herein, we show that HIV-1 specifically traffics through endocytic compartments contained within BC and directing such macrophage-to-macrophage viral transfers. Following clathrin-dependent viral entry, HIV-1 constituents bypass degradation by differential sorting from early to Rab11+ recycling endosomes and multivesicular bodies. Virus-containing endocytic viral cargoes propelled by myosin II through BC spread to neighboring uninfected cells. Disruption of endosomal motility with cytochalasin D, nocodasole and blebbistatin diminish intercellular viral spread. These data lead us to propose that HIV-1 hijacks macrophage endocytic and cytoskeletal machineries for high-speed cell-to-cell spread

DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans

The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has ?, ? and ? subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory ? subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ?75% of total ? subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 ? subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK ? subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved

A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs