Publications by authors named "Giovanni Iacono"

33 Publications

Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.

Dev Cell 2021 Feb 14;56(3):292-309.e9. Epub 2020 Dec 14.

Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA. Electronic address:

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.
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http://dx.doi.org/10.1016/j.devcel.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878434PMC
February 2021

Households as hotspots of Lassa fever? Assessing the spatial distribution of Lassa virus-infected rodents in rural villages of Guinea.

Emerg Microbes Infect 2020 Dec;9(1):1055-1064

Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.

The Natal multimammate mouse () is the reservoir host of Lassa virus (LASV), an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. While previous studies suggest that spillover risk is focal within rural villages due to the spatial behaviour of the rodents, the level of clustering was never specifically assessed. Nevertheless, detailed information on the spatial distribution of infected rodents would be highly valuable to optimize LASV-control campaigns, which are limited to rodent control or interrupting human-rodent contact considering that a human vaccine is not available. Here, we analysed data from a four-year field experiment to investigate whether LASV-infected rodents cluster in households in six rural villages in Guinea. Our analyses were based on the infection status (antibody or PCR) and geolocation of rodents (=864), and complemented with a phylogenetic analysis of LASV sequences (=119). We observed that the majority of infected rodents were trapped in a few houses (20%) and most houses were rodent-free at a specific point in time (60%). We also found that LASV strains circulating in a specific village were polyphyletic with respect to neighbouring villages, although most strains grouped together at the sub-village level and persisted over time. In conclusion, our results suggest that: (i) LASV spillover risk is heterogeneously distributed within villages in Guinea; (ii) viral elimination in one particular village is unlikely if rodents are not controlled in neighbouring villages. Such spatial information should be incorporated into eco-epidemiological models that assess the cost-efficiency of LASV control strategies.
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http://dx.doi.org/10.1080/22221751.2020.1766381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336995PMC
December 2020

Sampling time-dependent artifacts in single-cell genomics studies.

Genome Biol 2020 05 11;21(1):112. Epub 2020 May 11.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

Robust protocols and automation now enable large-scale single-cell RNA and ATAC sequencing experiments and their application on biobank and clinical cohorts. However, technical biases introduced during sample acquisition can hinder solid, reproducible results, and a systematic benchmarking is required before entering large-scale data production. Here, we report the existence and extent of gene expression and chromatin accessibility artifacts introduced during sampling and identify experimental and computational solutions for their prevention.
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http://dx.doi.org/10.1186/s13059-020-02032-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212672PMC
May 2020

Examining the influence of weather on rotavirus infection.

Lancet Planet Health 2019 06;3(6):e236-e237

School of Veterinary Medicine, Department of Veterinary Epidemiology and Public Health, University of Surrey, Surrey, UK.

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http://dx.doi.org/10.1016/S2542-5196(19)30093-2DOI Listing
June 2019

Single-cell transcriptomics unveils gene regulatory network plasticity.

Genome Biol 2019 06 4;20(1):110. Epub 2019 Jun 4.

CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, 08028, Barcelona, Spain.

Background: Single-cell RNA sequencing (scRNA-seq) plays a pivotal role in our understanding of cellular heterogeneity. Current analytical workflows are driven by categorizing principles that consider cells as individual entities and classify them into complex taxonomies.

Results: We devise a conceptually different computational framework based on a holistic view, where single-cell datasets are used to infer global, large-scale regulatory networks. We develop correlation metrics that are specifically tailored to single-cell data, and then generate, validate, and interpret single-cell-derived regulatory networks from organs and perturbed systems, such as diabetes and Alzheimer's disease. Using tools from graph theory, we compute an unbiased quantification of a gene's biological relevance and accurately pinpoint key players in organ function and drivers of diseases.

Conclusions: Our approach detects multiple latent regulatory changes that are invisible to single-cell workflows based on clustering or differential expression analysis, significantly broadening the biological insights that can be obtained with this leading technology.
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http://dx.doi.org/10.1186/s13059-019-1713-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547541PMC
June 2019

New methodologies for the estimation of population vulnerability to diseases: a case study of Lassa fever and Ebola in Nigeria and Sierra Leone.

Philos Trans R Soc Lond B Biol Sci 2019 07;374(1776):20180265

1 School of Veterinary Medicine, Daphne Jackson Road, University of Surrey , Guildford, Surrey GU2 7AL , UK.

Public health practitioners require measures to evaluate how vulnerable populations are to diseases, especially for zoonoses (i.e. diseases transmitted from animals to humans) given their pandemic potential. These measures would be valuable to support strategic and operational decision making and allocation of resources. Although vulnerability is well defined for natural hazards, for public health threats the concept remains undetermined. Here, we develop new methodologies to: (i) quantify the impact of zoonotic diseases and the capacity of countries to cope with these diseases, and (ii) combine these two measures (impact and capacity) into one overall vulnerability indicator. The adaptive capacity is calculated from estimations of disease mortality, although the method can be adapted for diseases with no or low mortality but high morbidity. As an example, we focused on the vulnerability of Nigeria and Sierra Leone to Lassa Fever and Ebola. We develop a simple analytical form that can be used to estimate vulnerability scores for different spatial units of interest, e.g. countries or regions. We show how some populations can be highly vulnerable despite low impact threats. We finally outline future research to more comprehensively inform vulnerability with the incorporation of relevant factors depicting local heterogeneities (e.g. bio-physical and socio-economic factors). This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.
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http://dx.doi.org/10.1098/rstb.2018.0265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558567PMC
July 2019

Seasonality and the effects of weather on Campylobacter infections.

BMC Infect Dis 2019 Mar 13;19(1):255. Epub 2019 Mar 13.

Statistics, Modelling and Economics Department, National Infection Service, Public Health England, 61, Colindale Avenue, London, NW9 5EQ, UK.

Background: Campylobacteriosis is a major public health concern. The weather factors that influence spatial and seasonal distributions are not fully understood.

Methods: To investigate the impacts of temperature and rainfall on Campylobacter infections in England and Wales, cases of Campylobacter were linked to local temperature and rainfall at laboratory postcodes in the 30 days before the specimen date. Methods for investigation included a comparative conditional incidence, wavelet, clustering, and time series analyses.

Results: The increase of Campylobacter infections in the late spring was significantly linked to temperature two weeks before, with an increase in conditional incidence of 0.175 cases per 100,000 per week for weeks 17 to 24; the relationship to temperature was not linear. Generalized structural time series model revealed that changes in temperature accounted for 33.3% of the expected cases of Campylobacteriosis, with an indication of the direction and relevant temperature range. Wavelet analysis showed a strong annual cycle with additional harmonics at four and six months. Cluster analysis showed three clusters of seasonality with geographic similarities representing metropolitan, rural, and other areas.

Conclusions: The association of Campylobacteriosis with temperature is likely to be indirect. High-resolution spatial temporal linkage of weather parameters and cases is important in improving weather associations with infectious diseases. The primary driver of Campylobacter incidence remains to be determined; other avenues, such as insect contamination of chicken flocks through poor biosecurity should be explored.
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http://dx.doi.org/10.1186/s12879-019-3840-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417031PMC
March 2019

Estimating human-to-human transmissibility of hepatitis A virus in an outbreak at an elementary school in China, 2011.

PLoS One 2018 24;13(9):e0204201. Epub 2018 Sep 24.

Chemical and Environmental Effects Centre for Radiation, Chemical and Environmental Hazards, Public Health England, London, United Kingdom.

Hepatitis A is caused by hepatitis A virus and occurs worldwide. Estimating the transmissibility, which is usually characterized by the basic reproductive number R0, the mean number of secondary infectious cases generated by a single primary infectious case introduced into a totally susceptible population, provides crucial information for the effort required to stop infection spreading. Hepatitis A virus is usually transmitted indirectly through contaminated food and environment. An outbreak from March to June 2011 was reported to have occurred at an elementary school of 698 pupils in China and it was found that the outbreak was due to direct transmission between school children. Based on the symptom onset date and the social contact network of the children, in this study we estimate the serial interval (i.e. the gap in symptom onset between an infectee and its infector) and use different statistical methods to estimate R0. Combining with the positivity of IgG antibodies tests, we develop a compartmental transmission dynamics model which includes both asymptomatic and symptomatic infections to estimate the overall R0. Our analysis suggests a serial interval of mean = 23.9 days and standard deviation = 20.9 days. The different statistical methods suggest estimates for R0 in the outbreak varying from 2.1 to 2.8, and the estimates from the transmission dynamics model are consistent with this range. Our estimates are in agreement with that from one study in England but are higher than that from one study in the United States. Our transmission dynamics model suggests that the proportion of symptomatic infections is about 9%, implying that there were about 344 asymptomatic infections along with the 32 observed symptomatic cases. Furthermore, it is shown that the inclusion of asymptomatic infection in the epidemic process increases the estimate of R0 but does not do so greatly provided that the proportion of symptomatic infections is constant over the outbreak and there is no difference in transmissibility between symptomatic and asymptomatic infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152969PMC
March 2019

Environmental limits of Rift Valley fever revealed using ecoepidemiological mechanistic models.

Proc Natl Acad Sci U S A 2018 07 18;115(31):E7448-E7456. Epub 2018 Jul 18.

Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge CB3 0ES, United Kingdom.

Vector-borne diseases (VBDs) of humans and domestic animals are a significant component of the global burden of disease and a key driver of poverty. The transmission cycles of VBDs are often strongly mediated by the ecological requirements of the vectors, resulting in complex transmission dynamics, including intermittent epidemics and an unclear link between environmental conditions and disease persistence. An important broader concern is the extent to which theoretical models are reliable at forecasting VBDs; infection dynamics can be complex, and the resulting systems are highly unstable. Here, we examine these problems in detail using a case study of Rift Valley fever (RVF), a high-burden disease endemic to Africa. We develop an ecoepidemiological, compartmental, mathematical model coupled to the dynamics of ambient temperature and water availability and apply it to a realistic setting using empirical environmental data from Kenya. Importantly, we identify the range of seasonally varying ambient temperatures and water-body availability that leads to either the extinction of mosquito populations and/or RVF (nonpersistent regimens) or the establishment of long-term mosquito populations and consequently, the endemicity of the RVF infection (persistent regimens). Instabilities arise when the range of the environmental variables overlaps with the threshold of persistence. The model captures the intermittent nature of RVF occurrence, which is explained as low-level circulation under the threshold of detection, with intermittent emergence sometimes after long periods. Using the approach developed here opens up the ability to improve predictions of the emergence and behaviors of epidemics of many other important VBDs.
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http://dx.doi.org/10.1073/pnas.1803264115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077718PMC
July 2018

bigSCale: an analytical framework for big-scale single-cell data.

Genome Res 2018 06 3;28(6):878-890. Epub 2018 May 3.

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.

Single-cell RNA sequencing (scRNA-seq) has significantly deepened our insights into complex tissues, with the latest techniques capable of processing tens of thousands of cells simultaneously. Analyzing increasing numbers of cells, however, generates extremely large data sets, extending processing time and challenging computing resources. Current scRNA-seq analysis tools are not designed to interrogate large data sets and often lack sensitivity to identify marker genes. With bigSCale, we provide a scalable analytical framework to analyze millions of cells, which addresses the challenges associated with large data sets. To handle the noise and sparsity of scRNA-seq data, bigSCale uses large sample sizes to estimate an accurate numerical model of noise. The framework further includes modules for differential expression analysis, cell clustering, and marker identification. A directed convolution strategy allows processing of extremely large data sets, while preserving transcript information from individual cells. We evaluated the performance of bigSCale using both a biological model of aberrant gene expression in patient-derived neuronal progenitor cells and simulated data sets, which underlines the speed and accuracy in differential expression analysis. To test its applicability for large data sets, we applied bigSCale to assess 1.3 million cells from the mouse developing forebrain. Its directed down-sampling strategy accumulates information from single cells into index cell transcriptomes, thereby defining cellular clusters with improved resolution. Accordingly, index cell clusters identified rare populations, such as reelin ()-positive Cajal-Retzius neurons, for which we report previously unrecognized heterogeneity associated with distinct differentiation stages, spatial organization, and cellular function. Together, bigSCale presents a solution to address future challenges of large single-cell data sets.
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http://dx.doi.org/10.1101/gr.230771.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991513PMC
June 2018

A comparison of weather variables linked to infectious disease patterns using laboratory addresses and patient residence addresses.

BMC Infect Dis 2018 04 27;18(1):198. Epub 2018 Apr 27.

Public Health England, London, UK.

Background: To understand the impact of weather on infectious diseases, information on weather parameters at patient locations is needed, but this is not always accessible due to confidentiality or data availability. Weather parameters at nearby locations are often used as a proxy, but the accuracy of this practice is not known.

Methods: Daily Campylobacter and Cryptosporidium cases across England and Wales were linked to local temperature and rainfall at the residence postcodes of the patients and at the corresponding postcodes of the laboratory where the patient's specimen was tested. The paired values of daily rainfall and temperature for the laboratory versus residence postcodes were interpolated from weather station data, and the results were analysed for agreement using linear regression. We also assessed potential dependency of the findings on the relative geographic distance between the patient's residence and the laboratory.

Results: There was significant and strong agreement between the daily values of rainfall and temperature at diagnostic laboratories with the values at the patient residence postcodes for samples containing the pathogens Campylobacter or Cryptosporidium. For rainfall, the R-squared was 0.96 for the former and 0.97 for the latter, and for maximum daily temperature, the R-squared was 0.99 for both. The overall mean distance between the patient residence and the laboratory was 11.9 km; however, the distribution of these distances exhibited a heavy tail, with some rare situations where the distance between the patient residence and the laboratory was larger than 500 km. These large distances impact the distributions of the weather variable discrepancies (i.e. the differences between weather parameters estimated at patient residence postcodes and those at laboratory postcodes), with discrepancies up to ±10 °C for the minimum and maximum temperature and 20 mm for rainfall. Nevertheless, the distributions of discrepancies (estimated separately for minimum and maximum temperature and rainfall), based on the cases where the distance between the patient residence and the laboratory was within 20 km, still exhibited tails somewhat longer than the corresponding exponential fits suggesting modest small scale variations in temperature and rainfall.

Conclusion: The findings confirm that, for the purposes of studying the relationships between meteorological variables and infectious diseases using data based on laboratory postcodes, the weather results are sufficiently similar to justify the use of laboratory postcode as a surrogate for domestic postcode. Exclusion of the small percentage of cases where there is a large distance between the residence and the laboratory could increase the precision of estimates, but there are generally strong associations between daily weather parameters at residence and laboratory.
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http://dx.doi.org/10.1186/s12879-018-3106-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923021PMC
April 2018

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.

Hum Mol Genet 2018 06;27(12):2138-2153

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67404 Illkirch, France.

The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.
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http://dx.doi.org/10.1093/hmg/ddy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985730PMC
June 2018

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome.

Nucleic Acids Res 2018 06;46(10):4950-4965

Radboud University, Department of Molecular Biology, Faculty of Science, 6500 HB Nijmegen, the Netherlands.

Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.
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http://dx.doi.org/10.1093/nar/gky196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007260PMC
June 2018

Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus.

Sci Rep 2017 12 22;7(1):18073. Epub 2017 Dec 22.

Radboud University, Department of Molecular Biology, Faculty of Science, 6500 HB, Nijmegen, The Netherlands.

The ability to assign expression patterns to the individual cell types that constitute a tissue is a major challenge. This especially applies to brain, given its plethora of different, functionally interconnected cell types. Here, we derived cell type-specific transcriptome signatures from existing single cell RNA data and integrated these signatures with a newly generated dataset of expression (bulk RNA-Seq) of the postnatal developing mouse hippocampus. This integrated analysis allowed us to provide a comprehensive and unbiased prediction of the differentiation drivers for 11 different hippocampal cell types and describe how the different cell types interact to support crucial developmental stages. Our results provide a reliable resource of predicted differentiation drivers and insights into the multifaceted aspects of the cells in hippocampus during development.
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http://dx.doi.org/10.1038/s41598-017-18287-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741714PMC
December 2017

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.

PLoS Genet 2017 Jul 13;13(7):e1006886. Epub 2017 Jul 13.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.
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http://dx.doi.org/10.1371/journal.pgen.1006886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531616PMC
July 2017

Challenges in developing methods for quantifying the effects of weather and climate on water-associated diseases: A systematic review.

PLoS Negl Trop Dis 2017 Jun 12;11(6):e0005659. Epub 2017 Jun 12.

European Centre for Environment and Human Health, University of Exeter Medical School, Truro, Cornwall, United Kingdom.

Infectious diseases attributable to unsafe water supply, sanitation and hygiene (e.g. Cholera, Leptospirosis, Giardiasis) remain an important cause of morbidity and mortality, especially in low-income countries. Climate and weather factors are known to affect the transmission and distribution of infectious diseases and statistical and mathematical modelling are continuously developing to investigate the impact of weather and climate on water-associated diseases. There have been little critical analyses of the methodological approaches. Our objective is to review and summarize statistical and modelling methods used to investigate the effects of weather and climate on infectious diseases associated with water, in order to identify limitations and knowledge gaps in developing of new methods. We conducted a systematic review of English-language papers published from 2000 to 2015. Search terms included concepts related to water-associated diseases, weather and climate, statistical, epidemiological and modelling methods. We found 102 full text papers that met our criteria and were included in the analysis. The most commonly used methods were grouped in two clusters: process-based models (PBM) and time series and spatial epidemiology (TS-SE). In general, PBM methods were employed when the bio-physical mechanism of the pathogen under study was relatively well known (e.g. Vibrio cholerae); TS-SE tended to be used when the specific environmental mechanisms were unclear (e.g. Campylobacter). Important data and methodological challenges emerged, with implications for surveillance and control of water-associated infections. The most common limitations comprised: non-inclusion of key factors (e.g. biological mechanism, demographic heterogeneity, human behavior), reporting bias, poor data quality, and collinearity in exposures. Furthermore, the methods often did not distinguish among the multiple sources of time-lags (e.g. patient physiology, reporting bias, healthcare access) between environmental drivers/exposures and disease detection. Key areas of future research include: disentangling the complex effects of weather/climate on each exposure-health outcome pathway (e.g. person-to-person vs environment-to-person), and linking weather data to individual cases longitudinally.
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http://dx.doi.org/10.1371/journal.pntd.0005659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481148PMC
June 2017

A Unified Framework for the Infection Dynamics of Zoonotic Spillover and Spread.

PLoS Negl Trop Dis 2016 09 2;10(9):e0004957. Epub 2016 Sep 2.

Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom.

A considerable amount of disease is transmitted from animals to humans and many of these zoonoses are neglected tropical diseases. As outbreaks of SARS, avian influenza and Ebola have demonstrated, however, zoonotic diseases are serious threats to global public health and are not just problems confined to remote regions. There are two fundamental, and poorly studied, stages of zoonotic disease emergence: 'spillover', i.e. transmission of pathogens from animals to humans, and 'stuttering transmission', i.e. when limited human-to-human infections occur, leading to self-limiting chains of transmission. We developed a transparent, theoretical framework, based on a generalization of Poisson processes with memory of past human infections, that unifies these stages. Once we have quantified pathogen dynamics in the reservoir, with some knowledge of the mechanism of contact, the approach provides a tool to estimate the likelihood of spillover events. Comparisons with independent agent-based models demonstrates the ability of the framework to correctly estimate the relative contributions of human-to-human vs animal transmission. As an illustrative example, we applied our model to Lassa fever, a rodent-borne, viral haemorrhagic disease common in West Africa, for which data on human outbreaks were available. The approach developed here is general and applicable to a range of zoonoses. This kind of methodology is of crucial importance for the scientific, medical and public health communities working at the interface between animal and human diseases to assess the risk associated with the disease and to plan intervention and appropriate control measures. The Lassa case study revealed important knowledge gaps, and opportunities, arising from limited knowledge of the temporal patterns in reporting, abundance of and infection prevalence in, the host reservoir.
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http://dx.doi.org/10.1371/journal.pntd.0004957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010258PMC
September 2016

Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling.

Neuron 2016 07 30;91(2):341-55. Epub 2016 Jun 30.

Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, the Netherlands. Electronic address:

Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra-syndrome-associated protein EHMT1 plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vitro and in vivo. Our findings suggest that H3K9me2-mediated changes in chromatin structure govern a repressive program that controls synaptic scaling.
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http://dx.doi.org/10.1016/j.neuron.2016.06.003DOI Listing
July 2016

Moving interdisciplinary science forward: integrating participatory modelling with mathematical modelling of zoonotic disease in Africa.

Infect Dis Poverty 2016 Feb 25;5:17. Epub 2016 Feb 25.

Geography and Environment, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.

This review outlines the benefits of using multiple approaches to improve model design and facilitate multidisciplinary research into infectious diseases, as well as showing and proposing practical examples of effective integration. It looks particularly at the benefits of using participatory research in conjunction with traditional modelling methods to potentially improve disease research, control and management. Integrated approaches can lead to more realistic mathematical models which in turn can assist with making policy decisions that reduce disease and benefit local people. The emergence, risk, spread and control of diseases are affected by many complex bio-physical, environmental and socio-economic factors. These include climate and environmental change, land-use variation, changes in population and people's behaviour. The evidence base for this scoping review comes from the work of a consortium, with the aim of integrating modelling approaches traditionally used in epidemiological, ecological and development research. A total of five examples of the impacts of participatory research on the choice of model structure are presented. Example 1 focused on using participatory research as a tool to structure a model. Example 2 looks at identifying the most relevant parameters of the system. Example 3 concentrates on identifying the most relevant regime of the system (e.g., temporal stability or otherwise), Example 4 examines the feedbacks from mathematical models to guide participatory research and Example 5 goes beyond the so-far described two-way interplay between participatory and mathematical approaches to look at the integration of multiple methods and frameworks. This scoping review describes examples of best practice in the use of participatory methods, illustrating their potential to overcome disciplinary hurdles and promote multidisciplinary collaboration, with the aim of making models and their predictions more useful for decision-making and policy formulation.
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http://dx.doi.org/10.1186/s40249-016-0110-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766706PMC
February 2016

Can insecticide-treated netting provide protection for Equids from Culicoides biting midges in the United Kingdom?

Parasit Vectors 2015 Nov 25;8:604. Epub 2015 Nov 25.

Vector-borne Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK.

Background: Biting midges of the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) cause a significant biting nuisance to equines and are responsible for the biological transmission of African horse sickness virus (AHSV). While currently restricted in distribution to sub-Saharan Africa, AHSV has a history of emergence into southern Europe and causes one of the most lethal diseases of horses and other species of Equidae. In the event of an outbreak of AHSV, the use of insecticide treated nets (ITNs) to screen equine accomodation is recommended by competent authorities including the Office International des Épizooties (OIE) in order to reduce vector-host contact.

Methods: Seven commercially avaliable pyrethroid insecticides and three repellent compounds, all of which are licensed for amateur use, were assessed in modified World Health Organization (WHO) cone bioassay trials in the laboratory using a colony line of Culicoides nubeculosus (Meigen), 1830. Two field trials were subsequently conducted to test the efficiency of treated net screens in preventing entry of Culicoides.

Results: A formulation of cypermethrin (0.15 % w/w) and pyrethrins (0.2 % w/w) (Tri-Tec 14®, LS Sales (Farnham) Ltd, Bloxham, UK) applied to black polyvinyl-coated polyester insect screen (1.6 mm aperture; 1.6 mm thickness) inflicted 100 % mortality on batches of C. nubeculosus following a three minute exposure in the WHO cone bioassays at 1, 7 and 14 days post-treatment. Tri-Tec 14® outperformed all other treatments tested and was subsequently selected for use in field trials. The first trial demonstrated that treated screens placed around an ultraviolet light-suction trap entirely prevented Culicoides being collected, despite their collection in identical traps with untreated screening or no screening. The second field trial examined entry of Culicoides into stables containing horses and found that while the insecticide treated screens reduced entry substantially, there was still a small risk of exposure to biting.

Conclusions: Screened stables can be utilised as part of an integrated control program in the event of an AHSV outbreak in order to reduce vector-host contact and may also be applicable to protection of horses from Culicoides during transport.
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http://dx.doi.org/10.1186/s13071-015-1182-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660720PMC
November 2015

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

Hum Mol Genet 2015 Dec 16;24(23):6736-55. Epub 2015 Sep 16.

Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France and Université de Strasbourg, Illkirch, France

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.
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http://dx.doi.org/10.1093/hmg/ddv380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634377PMC
December 2015

Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of lassa fever.

PLoS Negl Trop Dis 2015 Jan 8;9(1):e3398. Epub 2015 Jan 8.

Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom.

Background: Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions.

Methodology/principal Findings: Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Formula: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals ('super-spreaders'), as we found only [Formula: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Formula: see text], with a maximum value up to [Formula: see text].

Conclusions/significance: This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.
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http://dx.doi.org/10.1371/journal.pntd.0003398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288732PMC
January 2015

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus.

PLoS One 2013 23;8(7):e68078. Epub 2013 Jul 23.

Department of Functional Analysis, International School for Advanced Studies, Trieste, Italy.

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 µM gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10∶90] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720722PMC
March 2014

Where are the horses? With the sheep or cows? Uncertain host location, vector-feeding preferences and the risk of African horse sickness transmission in Great Britain.

J R Soc Interface 2013 Jun 17;10(83):20130194. Epub 2013 Apr 17.

Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

Understanding the influence of non-susceptible hosts on vector-borne disease transmission is an important epidemiological problem. However, investigation of its impact can be complicated by uncertainty in the location of the hosts. Estimating the risk of transmission of African horse sickness (AHS) in Great Britain (GB), a virus transmitted by Culicoides biting midges, provides an insightful example because: (i) the patterns of risk are expected to be influenced by the presence of non-susceptible vertebrate hosts (cattle and sheep) and (ii) incomplete information on the spatial distribution of horses is available because the GB National Equine Database records owner, rather than horse, locations. Here, we combine land-use data with available horse owner distributions and, using a Bayesian approach, infer a realistic distribution for the location of horses. We estimate the risk of an outbreak of AHS in GB, using the basic reproduction number (R0), and demonstrate that mapping owner addresses as a proxy for horse location significantly underestimates the risk. We clarify the role of non-susceptible vertebrate hosts by showing that the risk of disease in the presence of many hosts (susceptible and non-susceptible) can be ultimately reduced to two fundamental factors: first, the abundance of vectors and how this depends on host density, and, second, the differential feeding preference of vectors among animal species.
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http://dx.doi.org/10.1098/rsif.2013.0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645429PMC
June 2013

A rate-distortion theory for gene regulatory networks and its application to logic gate consistency.

Bioinformatics 2013 May 6;29(9):1166-73. Epub 2013 Mar 6.

SISSA, Int. School for Advanced Studies, via Bonomea 265, 34136 Trieste, Italy.

Motivation: A gene regulatory network in which the modes (activation/inhibition) of the transcriptional regulations are known and in which gene expression assumes boolean values can be treated as a system of linear equations over a binary field, i.e. as a constraint satisfaction problem for an information code.

Results: For currently available gene networks, we show in this article that the distortion associated with the corresponding information code is much lower than expected from null models, and that it is close to (when not lower than) the Shannon bound determined by the rate-distortion theorem. This corresponds to saying that the distribution of regulatory modes is highly atypical in the networks, and that this atypicality greatly helps in avoiding contradictory transcriptional actions. Choosing a boolean formalism to represent the gene networks, we also show how to formulate criteria for the selection of gates that maximize the compatibility with the empirical information available on the transcriptional regulatory modes. Proceeding in this way, we obtain in particular that non-canalizing gates are upper-bounded by the distortion, and hence that the boolean gene networks are more canalizing than expected from null models.
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http://dx.doi.org/10.1093/bioinformatics/btt116DOI Listing
May 2013

Durable resistance to crop pathogens: an epidemiological framework to predict risk under uncertainty.

PLoS Comput Biol 2013 17;9(1):e1002870. Epub 2013 Jan 17.

Department of Veterinary Medicine, Disease Dynamics Unit, University of Cambridge, Cambridge, United Kingdom.

Increasing the durability of crop resistance to plant pathogens is one of the key goals of virulence management. Despite the recognition of the importance of demographic and environmental stochasticity on the dynamics of an epidemic, their effects on the evolution of the pathogen and durability of resistance has not received attention. We formulated a stochastic epidemiological model, based on the Kramer-Moyal expansion of the Master Equation, to investigate how random fluctuations affect the dynamics of an epidemic and how these effects feed through to the evolution of the pathogen and durability of resistance. We focused on two hypotheses: firstly, a previous deterministic model has suggested that the effect of cropping ratio (the proportion of land area occupied by the resistant crop) on the durability of crop resistance is negligible. Increasing the cropping ratio increases the area of uninfected host, but the resistance is more rapidly broken; these two effects counteract each other. We tested the hypothesis that similar counteracting effects would occur when we take account of demographic stochasticity, but found that the durability does depend on the cropping ratio. Secondly, we tested whether a superimposed external source of stochasticity (for example due to environmental variation or to intermittent fungicide application) interacts with the intrinsic demographic fluctuations and how such interaction affects the durability of resistance. We show that in the pathosystem considered here, in general large stochastic fluctuations in epidemics enhance extinction of the pathogen. This is more likely to occur at large cropping ratios and for particular frequencies of the periodic external perturbation (stochastic resonance). The results suggest possible disease control practises by exploiting the natural sources of stochasticity.
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http://dx.doi.org/10.1371/journal.pcbi.1002870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547817PMC
June 2013

The evolution of plant pathogens in response to host resistance: factors affecting the gain from deployment of qualitative and quantitative resistance.

J Theor Biol 2012 Jul 1;304:152-63. Epub 2012 Apr 1.

Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, United Kingdom.

Disease resistance genes are valuable natural resources which should be deployed in a way which maximises the gain to crop productivity before they lose efficacy. Here we present a general epidemiological model for plant diseases, formulated to study the evolution of phenotypic traits of plant pathogens in response to host resistance. The model was used to analyse how the characteristics of the disease resistance, and the method of deployment, affect the size and duration of the gain. The gain obtained from growing a resistant cultivar, compared to a susceptible cultivar, was quantified as the increase in green canopy area resulting from control of foliar disease, integrated over many years-termed 'Healthy Area Duration (HAD) Gain'. Previous work has suggested that the effect of crop ratio (the proportion of land area occupied by the resistant crop) on the gain from qualitative (gene-for-gene) resistance is negligible. Increasing the crop ratio increases the area of uninfected host, but the resistance is more rapidly broken; these two effects counteract each other. We tested the hypothesis that similar counteracting effects would occur for quantitative, multi-genic resistance, but found that the HAD Gain increased at higher crop ratios. Then we tested the hypothesis that the gain from quantitative host resistance could differ depending on the life-cycle component (sporulation rate or infection efficiency) constrained by the resistance. For the patho-system considered, a quantitative resistant cultivar that reduced the infection efficiency gave a greater HAD Gain than a cultivar that reduced sporulation rate, despite having equivalent transmission rates.
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http://dx.doi.org/10.1016/j.jtbi.2012.03.033DOI Listing
July 2012

Computing global structural balance in large-scale signed social networks.

Proc Natl Acad Sci U S A 2011 Dec 13;108(52):20953-8. Epub 2011 Dec 13.

International School for Advanced Studies, via Bonomea 265, 34136 Trieste, Italy.

Structural balance theory affirms that signed social networks (i.e., graphs whose signed edges represent friendly/hostile interactions among individuals) tend to be organized so as to avoid conflictual situations, corresponding to cycles of negative parity. Using an algorithm for ground-state calculation in large-scale Ising spin glasses, in this paper we compute the global level of balance of very large online social networks and verify that currently available networks are indeed extremely balanced. This property is explainable in terms of the high degree of skewness of the sign distributions on the nodes of the graph. In particular, individuals linked by a large majority of negative edges create mostly "apparent disorder," rather than true "frustration."
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http://dx.doi.org/10.1073/pnas.1109521108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248482PMC
December 2011

Decompositions of large-scale biological systems based on dynamical properties.

Bioinformatics 2012 Jan 9;28(1):76-83. Epub 2011 Nov 9.

CRS4 Bioinformatica, Loc. Piscina Manna, 09010 Pula (CA), Italy.

Motivation: Given a large-scale biological network represented as an influence graph, in this article we investigate possible decompositions of the network aimed at highlighting specific dynamical properties.

Results: The first decomposition we study consists in finding a maximal directed acyclic subgraph of the network, which dynamically corresponds to searching for a maximal open-loop subsystem of the given system. Another dynamical property investigated is strong monotonicity. We propose two methods to deal with this property, both aimed at decomposing the system into strongly monotone subsystems, but with different structural characteristics: one method tends to produce a single large strongly monotone component, while the other typically generates a set of smaller disjoint strongly monotone subsystems.

Availability: Original heuristics for the methods investigated are described in the article.

Contact: altafini@sissa.it
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http://dx.doi.org/10.1093/bioinformatics/btr620DOI Listing
January 2012

Monotonicity, frustration, and ordered response: an analysis of the energy landscape of perturbed large-scale biological networks.

BMC Syst Biol 2010 Jun 10;4:83. Epub 2010 Jun 10.

SISSA-ISAS, International School for Advanced Studies, Trieste, Italy.

Background: For large-scale biological networks represented as signed graphs, the index of frustration measures how far a network is from a monotone system, i.e., how incoherently the system responds to perturbations.

Results: In this paper we find that the frustration is systematically lower in transcriptional networks (modeled at functional level) than in signaling and metabolic networks (modeled at stoichiometric level). A possible interpretation of this result is in terms of energetic cost of an interaction: an erroneous or contradictory transcriptional action costs much more than a signaling/metabolic error, and therefore must be avoided as much as possible. Averaging over all possible perturbations, however, we also find that unlike for transcriptional networks, in the signaling/metabolic networks the probability of finding the system in its least frustrated configuration tends to be high also in correspondence of a moderate energetic regime, meaning that, in spite of the higher frustration, these networks can achieve a globally ordered response to perturbations even for moderate values of the strength of the interactions. Furthermore, an analysis of the energy landscape shows that signaling and metabolic networks lack energetic barriers around their global optima, a property also favouring global order.

Conclusion: In conclusion, transcriptional and signaling/metabolic networks appear to have systematic differences in both the index of frustration and the transition to global order. These differences are interpretable in terms of the different functions of the various classes of networks.
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http://dx.doi.org/10.1186/1752-0509-4-83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909160PMC
June 2010