BrainSignals Revisited: Simplifying a Computational Model of Cerebral Physiology

Multimodal monitoring of brain state is important both for the investigation of healthy cerebral physiology and to inform clinical decision making in conditions of injury and disease. Near-infrared spectroscopy is an instrument modality that allows non-invasive measurement of several physiological variables of clinical interest, notably haemoglobin oxygenation and the redox state of the metabolic enzyme cytochrome c oxidase. Interpreting such measurements requires the integration of multiple signals from different sources to try to understand the physiological states giving rise to them. We have previously published several computational models to assist with such interpretation. Like many models in the realm of Systems Biology, these are complex and dependent on many parameters that can be difficult or impossible to measure precisely. Taking one such model, BrainSignals, as a starting point, we have developed several variant models in which specific regions of complexity are substituted with much simpler linear approximations. We demonstrate that model behaviour can be maintained whilst achieving a significant reduction in complexity, provided that the linearity assumptions hold. The simplified models have been tested for applicability with simulated data and experimental data from healthy adults undergoing a hypercapnia challenge, but relevance to different physiological and pathophysiological conditions will require specific testing. In conditions where the simplified models are applicable, their greater efficiency has potential to allow their use at the bedside to help interpret clinical data in near real-time

A mechanistic model for naive CD4 T cell homeostasis in healthy adults and children

The size and composition of the T lymphocyte compartment is subject to strict homeostatic regulation and is remarkably stable throughout life in spite of variable dynamics in cell production and death during T cell development and immune responses. Homeostasis is achieved by careful orchestration of lymphocyte survival and cell division. New T cells are generated from the thymus and the number of peripheral T cells is regulated by controlling survival and proliferation. How these processes combine is however very complex. Thymic output increases in the first year of life and then decreases but is crucial for establishing repertoire diversity. Proliferation of new naive T cells plays a crucial role for maintaining numbers but at a potential cost to TCR repertoire diversity. A mechanistic two-compartment model of T cell homeostasis is described here that includes specific terms for thymic output, cell proliferation, and cell death of both resting and dividing cells. The model successfully predicts the homeostatic set point for T cells in adults and identifies variables that determine the total number of T cells. It also accurately predicts T cell numbers in children in early life despite rapid changes in thymic output and growth over this period

Simulating NIRS and MRS Measurements During Cerebral Hypoxia-Ischaemia in Piglets Using a Computational Model

We present a group analysis of the changes in cerebral haemodynamics, and the oxidation state of cytochrome-c-oxidase measured using broadband near-infrared spectroscopy (NIRS) and intracellular pH measured by phosphorous ((31)P) magnetic resonance spectroscopy (MRS) during and after cerebral hypoxia-ischaemia (HI) in 15 piglets. We use a previously published computational model of cerebral metabolism in the piglet [1] to integrate these measurements and simulate HI. We successfully simulate changes in cellular metabolism including shifts in intracellular pH observed in the piglet brain during HI. In this process, we optimise physiological parameters in the model identified through sensitivity analysis (such as the rate of glucose metabolism and intracellular lactate concentration), to fit simulated and measured data. The model fits the data reasonably and suggests a 20 % drop in glucose consumption, a ~65 % increase in lactate concentration and ~35 % drop in the cerebral metabolic rate of oxygen (CMRO₂) during HI

The influence of carbon nanotubes on the combustion toxicity of PP/intumescent flame retardant composites

In recent years, carbon nanotubes (CNTs) have emerged as a promising candidate for improving the flame retardancy of polymer materials, as well as other physical properties. However, few researches have been focused on the influence of this nanoscale material on the combustion toxicity of polymer composites during combustion. In this work, the fire toxicity of polypropylene (PP) composites with intumescent flame retardants (IFRs) and CNTs has been investigated by a Purser Furnace apparatus, which is called steady state tube furnace (SSTF) and enables different fire stages to be created. The Thermo gravimetric analyzer (TGA) and derivative thermo gravimetric analysis (DTG) data indicate that the thermal stability of PP composites was increased by the addition of IFRs or CNTs. However, the SSTF results show that PP samples with IFR or CNTs or both, produced much more carbon monoxide (CO) compared to neat PP during all fire stages, resulting in a much lower CO2/CO ratio. Furthermore, an interesting finding is that the effect of CNTs on the smoke production and CxHy yield of the PP samples during the combustion changes with the combustion equivalence ratio. It indicates that the presence of CNTs promote the formation of smoke particulates from hydrocarbon, but this effect only exist when oxygen supply is not adequate. It is also concluded that the air ventilation and combustion temperature play significant roles in the fire effluent production of PP samples and the morphology of soot particulates

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. Copyright

Genetic Diversity and Dispersal of DENGUE Virus among Three Main Island Groups of the Philippines during 2015-2017

Dengue has been one of the major public health concerns in the Philippines for more than a century. The annual dengue case burden has been increasing in recent years, exceeding 200,000 in 2015 and 2019. However, there is limited information on the molecular epidemiology of dengue in the Philippines. We, therefore, conducted a study to understand the genetic composition and dispersal of DENV in the Philippines from 2015 to 2017 under UNITEDengue. Our analyses included 377 envelope (E) gene sequences of all 4 serotypes obtained from infections in 3 main island groups (Luzon, Visayas, and Mindanao) of the Philippines. The findings showed that the overall diversity of DENV was generally low. DENV-1 was relatively more diverse than the other serotypes. Virus dispersal was evident among the three main island groups, but each island group demonstrated a distinct genotype composition. These observations suggested that the intensity of virus dispersal was not substantive enough to maintain a uniform heterogeneity among island groups so that each island group behaved as an independent epidemiological unit. The analyses suggested Luzon as one of the major sources of DENV emergence and CAR, Calabarzon, and CARAGA as important hubs of virus dispersal in the Philippines. Our findings highlight the importance of virus surveillance and molecular epidemiological analyses to gain deep insights into virus diversity, lineage dominance, and dispersal patterns that could assist in understanding the epidemiology and transmission risk of dengue in endemic regions

Chikungunya virus adaptation to Aedes albopictus mosquitoes does not correlate with acquisition of cholesterol dependence or decreased pH threshold for fusion reaction

<p>Abstract</p> <p>Background</p> <p>Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus that recently caused several large scale outbreaks/epidemics of arthritic disease in tropics of Africa, Indian Ocean basin and South-East Asia. This re-emergence event was facilitated by genetic adaptation (E1-A226V substitution) of CHIKV to a newly significant mosquito vector for this virus; <it>Aedes albopictus</it>. However, the molecular mechanism explaining the positive effect of the E1-A226V mutation on CHIKV fitness in this vector remains largely unknown. Previously we demonstrated that the E1-A226V substitution is also associated with attenuated CHIKV growth in cells depleted by cholesterol.</p> <p>Methods</p> <p>In this study, using a panel of CHIKV clones that varies in sensitivity to cholesterol, we investigated the possible relationship between cholesterol dependence and <it>Ae. albopictus </it>infectivity.</p> <p>Results</p> <p>We demonstrated that there is no clear mechanistic correlation between these two phenotypes. We also showed that the E1-A226V mutation increases the pH dependence of the CHIKV fusion reaction; however, subsequent genetic analysis failed to support an association between CHIKV dependency on lower pH, and mosquito infectivity phenotypes.</p> <p>Conclusion</p> <p>the E1-A226V mutation probably acts at different steps of the CHIKV life cycle, affecting multiple functions of the virus.</p

Fungal diversity notes 253–366: taxonomic and phylogenetic contributions to fungal taxa

Notes on 113 fungal taxa are compiled in this paper, including 11 new genera, 89 new species, one new subspecies, three new combinations and seven reference specimens. A wide geographic and taxonomic range of fungal taxa are detailed. In the Ascomycota the new genera Angustospora (Testudinaceae), Camporesia (Xylariaceae), Clematidis, Crassiparies (Pleosporales genera incertae sedis), Farasanispora, Longiostiolum (Pleosporales genera incertae sedis), Multilocularia (Parabambusicolaceae), Neophaeocryptopus (Dothideaceae), Parameliola (Pleosporales genera incertae sedis), and Towyspora (Lentitheciaceae) are introduced. Newly introduced species are Angustospora nilensis, Aniptodera aquibella, Annulohypoxylon albidiscum, Astrocystis thailandica, Camporesia sambuci, Clematidis italica, Colletotrichum menispermi, C. quinquefoliae, Comoclathris pimpinellae, Crassiparies quadrisporus, Cytospora salicicola, Diatrype thailandica, Dothiorella rhamni, Durotheca macrostroma, Farasanispora avicenniae, Halorosellinia rhizophorae, Humicola koreana, Hypoxylon lilloi, Kirschsteiniothelia tectonae, Lindgomyces okinawaensis, Longiostiolum tectonae, Lophiostoma pseudoarmatisporum, Moelleriella phukhiaoensis, M. pongdueatensis, Mucoharknessia anthoxanthi, Multilocularia bambusae, Multiseptospora thysanolaenae, Neophaeocryptopus cytisi, Ocellularia arachchigei, O. ratnapurensis, Ochronectria thailandica, Ophiocordyceps karstii, Parameliola acaciae, P. dimocarpi, Parastagonospora cumpignensis, Pseudodidymosphaeria phlei, Polyplosphaeria thailandica, Pseudolachnella brevifusiformis, Psiloglonium macrosporum, Rhabdodiscus albodenticulatus, Rosellinia chiangmaiensis, Saccothecium rubi, Seimatosporium pseudocornii, S. pseudorosae, Sigarispora ononidis and Towyspora aestuari. New combinations are provided for Eutiarosporella dactylidis (sexual morph described and illustrated) and Pseudocamarosporium pini. Descriptions, illustrations and / or reference specimens are designated for Aposphaeria corallinolutea, Cryptovalsa ampelina, Dothiorella vidmadera, Ophiocordyceps formosana, Petrakia echinata, Phragmoporthe conformis and Pseudocamarosporium pini. The new species of Basidiomycota are Agaricus coccyginus, A. luteofibrillosus, Amanita atrobrunnea, A. digitosa, A. gleocystidiosa, A. pyriformis, A. strobilipes, Bondarzewia tibetica, Cortinarius albosericeus, C. badioflavidus, C. dentigratus, C. duboisensis, C. fragrantissimus, C. roseobasilis, C. vinaceobrunneus, C. vinaceogrisescens, C. wahkiacus, Cyanoboletus hymenoglutinosus, Fomitiporia atlantica, F. subtilissima, Ganoderma wuzhishanensis, Inonotus shoreicola, Lactifluus armeniacus, L. ramipilosus, Leccinum indoaurantiacum, Musumecia alpina, M. sardoa, Russula amethystina subp. tengii and R. wangii are introduced. Descriptions, illustrations, notes and / or reference specimens are designated for Clarkeinda trachodes, Dentocorticium ussuricum, Galzinia longibasidia, Lentinus stuppeus and Leptocorticium tenellum. The other new genera, species new combinations are Anaeromyces robustus, Neocallimastix californiae and Piromyces finnis from Neocallimastigomycota, Phytophthora estuarina, P. rhizophorae, Salispina, S. intermedia, S. lobata and S. spinosa from Oomycota, and Absidia stercoraria, Gongronella orasabula, Mortierella calciphila, Mucor caatinguensis, M. koreanus, M. merdicola and Rhizopus koreanus in Zygomycota

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe