A computational framework for gene regulatory network inference that combines multiple methods and datasets

<p>Abstract</p> <p>Background</p> <p>Reverse engineering in systems biology entails inference of gene regulatory networks from observational data. This data typically include gene expression measurements of wild type and mutant cells in response to a given stimulus. It has been shown that when more than one type of experiment is used in the network inference process the accuracy is higher. Therefore the development of generally applicable and effective methodologies that embed multiple sources of information in a single computational framework is a worthwhile objective.</p> <p>Results</p> <p>This paper presents a new method for network inference, which uses multi-objective optimisation (MOO) to integrate multiple inference methods and experiments. We illustrate the potential of the methodology by combining ODE and correlation-based network inference procedures as well as time course and gene inactivation experiments. Here we show that our methodology is effective for a wide spectrum of data sets and method integration strategies.</p> <p>Conclusions</p> <p>The approach we present in this paper is flexible and can be used in any scenario that benefits from integration of multiple sources of information and modelling procedures in the inference process. Moreover, the application of this method to two case studies representative of bacteria and vertebrate systems has shown potential in identifying key regulators of important biological processes.</p

Maternal gaze to the infant face: effects of infant age and facial configuration during mother-infant engagement in the first nine weeks

Background Adult gaze plays an important role in early infant development, and infants are highly sensitive to its presence and direction. Little is known, however, about how adults look at infants while interacting with them. Using eye-tracking technology, this study investigated maternal gaze during naturalistic interactions, and how it was influenced by infant age, focusing on the transition from the first to the second month when social expressiveness emerges, and by infant facial configuration, focusing on the effect of cleft lip. Methods Thirty infants (10 with a cleft lip), and their mothers, were seen at 1, 3, 5, 7, and 9 weeks. Mothers were asked to interact with their infants while wearing eye-tracking glasses. Fixation duration and count were calculated for general (infant face, body, and surrounding environment), and infant facial (eyes, mouth, other) areas. Results At all ages, mothers gazed almost exclusively towards their infant’s face, but this was reduced in the presence of a cleft lip. Within the infant’s face, the eyes attracted the greatest attention, for all mothers, at all ages. From the first to the second month, all mothers increased their visual attention towards their infant’s mouth. Regardless of infant age, the presence of a cleft lip was associated with decreased maternal gaze to the infant’s mouth. Conclusions This study provides novel findings concerning maternal gaze to infant faces during naturalistic interactions. Maternal gaze changes with infant age, in line with established shifts in social development, and according to infant facial configuration. Decreased gaze to the mouth area associated with infant cleft lip might affect maternal responsiveness, and suggests new dimensions to target in supporting these mothers

The effects of maternal mirroring on the development of infant social expressiveness: the case of infant cleft lip

Parent-infant social interactions start early in development, with infants showing active communicative expressions by just two months. A key question is how this social capacity develops. Maternal mirroring of infant expressions is considered an important, intuitive, parenting response, but evidence is sparse in the first two months concerning the conditions under which mirroring occurs and its developmental sequelae, including in clinical samples where the infant’s social expressiveness may be affected. We investigated these questions by comparing the development of mother-infant interactions between a sample where the infant had cleft lip and a normal, unaffected, comparison sample. We videotaped dyads in their homes five times from one to ten weeks and used a microanalytic coding scheme for maternal and infant behaviours, including infant social expressions, and maternal mirroring and marking responses. We also recorded maternal gaze to the infant, using eye-tracking glasses. Although infants with cleft lip did show communicative behaviours, the rate of their development was slower than in comparison infants. This group difference was mediated by a lower rate of mirroring of infant expressions by mothers of infants with cleft lip; this effect was, in turn, partly accounted for by reduced gaze to the infant’s mouth, although the clarity of infant social expressions (indexed by cleft severity) and maternal self-blame regarding the cleft were also influential. Results indicate the robustness of parent-infant interactions but also their sensitivity to specific variations in interactants’ appearance and behaviour. Parental mirroring appears critical in infant social development, likely supported by the mirror neuron system and underlying clinical and, possibly, cultural differences in infant behaviour. These findings suggest new avenues for clinical intervention

Exploring Black and South Asian women's experiences of help-seeking and engagement in perinatal mental health services in the UK

Background and aims: In the United Kingdom (UK), Black and South Asian women are less likely than White British women to access support from perinatal mental health services, despite experiencing similar, or higher, levels of distress. This inequality needs to be understood and remedied. The aim of this study was to answer two questions: how do Black and South Asian women experience (1) access to perinatal mental health services and (2) care received from perinatal mental health services? Method: Semi-structured interviews were conducted with Black and South Asian women (n = 37), including four women who were interviewed with an interpreter. Interviews were recorded and transcribed line-by-line. Data were analyzed using framework analysis, by an ethnically diverse multidisciplinary team of clinicians, researchers and people with lived experience of perinatal mental illness. Results: Participants described a complex interplay of factors that impacted on seeking, and receiving help, and benefiting from services. Four themes emerged that captured the highly varied experiences of individuals: (1) Self-identity, social expectations and different attributions of distress deter help-seeking; (2) Hidden and disorganized services impede getting support; (3) The role of curiosity, kindness and flexibility in making women feel heard, accepted and supported by clinicians; (4) A shared cultural background may support or hinder trust and rapport. Conclusion: Women described a wide range of experiences and a complex interplay of factors impacting access to, and experience of, services. Women described services as giving them strength and also leaving them disappointed and confused about where to get help. The main barriers to access were attributions related to mental distress, stigma, mistrust and lack of visibility of services, and organizational gaps in the referral process. These findings describe that many women feel heard, and supported by services, reporting that services provide a high quality of care that was inclusive of diverse experiences and understandings of mental health problems. Transparency around what PMHS are, and what support is available would improve the accessibility of PMHS

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease

BACKGROUND: The development of disease-modifying therapies for Alzheimer’s disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors. We have documented the expression pattern of mTOR regulated genes in the frontal cortex of Alzheimer’s disease patients. We have also examined the functional integrity of mTOR signaling in peripheral lymphocytes in Alzheimer’s disease patients relative to healthy controls. RESULTS: In the brain mTOR is seen to control molecular functions related to cell cycle regulation, cell death and several metabolic pathways. These downstream elements of the mTOR signaling cascade are deregulated in the brain of Alzheimer’s disease patients well before the development of pathology. This dysregulation of the mTOR downstream signaling cascade is not restricted to the brain but appears to be systemic and can be detected in peripheral lymphocytes as a reduced Rapamycin response. CONCLUSIONS: The dysfunction of the signaling pathways downstream of mTOR may represent a risk factor for Alzheimer’s disease and is independent of the ApoE status of the patients. We have also identified the molecular substrates of the beneficial effects of Rapamycin on the nervous system. We believe that these results can further inform the development of clinical predictive tests for the risk of Alzheimer’s disease in patients with mild cognitive impairment

Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication

Hepatitis C virus (HCV) is a major cause of global morbidity, causing chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. The liver is a large and complex organ containing multiple cell types, including hepatocytes, sinusoidal endothelial cells (LSEC), Kupffer cells, and biliary epithelial cells. Hepatocytes are the major reservoir supporting HCV replication; however, the role of nonparenchymal cells in the viral lifecycle remains largely unexplored. LSEC secrete factors that promote HCV infection and transcript analysis identified bone morphogenetic protein 4 (BMP4) as a candidate endothelial-expressed proviral molecule. Recombinant BMP4 increased HCV replication and neutralization of BMP4 abrogated the proviral activity of LSEC-conditioned media. Importantly, BMP4 expression was negatively regulated by vascular endothelial growth factor A (VEGF-A) by way of a VEGF receptor-2 (VEGFR-2) primed activation of p38 MAPK. Consistent with our in vitro observations, we demonstrate that in normal liver VEGFR-2 is activated and BMP4 expression is suppressed. In contrast, in chronic liver disease including HCV infection where there is marked endothelial cell proliferation, we observed reduced endothelial cell VEGFR-2 activation and a concomitant increase in BMP4 expression. Conclusion: These studies identify a role for LSEC and BMP4 in HCV infection and highlight BMP4 as a new therapeutic target for treating individuals with liver disease

Riparian buffers can help mitigate biodiversity declines in oil palm agriculture

Agricultural expansion drives biodiversity decline in forested tropical regions. Consequently, it is important to understand the conservation value of remnant forest in production landscapes. In a tropical landscape dominated by oil palm we characterized faunal communities across eight taxa occurring within riparian forest buffers, which are legally protected alongside rivers, and compared them to nearby recovering logged forest. Buffer width was the main predictor of species richness and abundance, with widths of 40-100 m on each side of the river supporting broadly equivalent levels of biodiversity to logged forest. However, width responses varied markedly among taxa, and buffers often lacked forest-dependent species. Much wider buffers than are currently mandated are needed to safeguard most species. The largest biodiversity gains are achieved by increasing relatively narrow buffers. To provide optimal conservation outcomes in tropical production landscapes we encourage policymakers to prescribe width requirements for key taxa and different landscape contexts.Newton-Ungku Omar Fund (grants 216433953, 537134717) – delivered by the British Council and funded by the UK Department for Business, Energy and Industrial Strategy and the Malaysian Industry-Government Group for High Technology – as well as the UK Natural Environment Research Council (NE/K016407/1, NE/K016261/1; https://lombok.nerc-hmtf.info/). MJS was supported by a Research Leadership Award from the Leverhulme Trust

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Quantifying and addressing the prevalence and bias of study designs in the environmental and social sciences

Building trust in science and evidence-based decision-making depends heavily on the credibility of studies and their findings. Researchers employ many different study designs that vary in their risk of bias to evaluate the true effect of interventions or impacts. Here, we empirically quantify, on a large scale, the prevalence of different study designs and the magnitude of bias in their estimates. Randomised designs and controlled observational designs with pre-intervention sampling were used by just 23% of intervention studies in biodiversity conservation, and 36% of intervention studies in social science. We demonstrate, through pairwise within-study comparisons across 49 environmental datasets, that these types of designs usually give less biased estimates than simpler observational designs. We propose a model-based approach to combine study estimates that may suffer from different levels of study design bias, discuss the implications for evidence synthesis, and how to facilitate the use of more credible study designs.Fil: Christie, Alec P.. University of Cambridge; Reino UnidoFil: Abecasis, David. Universidad de Algarve. Centro de Ciencias del Mar; PortugalFil: Adjeroud, Mehdi. Université de Perpignan; Francia. Institut de Recherche Pour Le Developpement; FranciaFil: Alonso, Juan Carlos. Consejo Superior de Investigaciones Científicas. Museo Nacional de Ciencias Naturales; EspañaFil: Amano, Tatsuya. University of Queensland; AustraliaFil: Anton, Alvaro. Universidad del País Vasco. Facultad de Educación de Bilbao; EspañaFil: Baldigo, Barry P.. United States Geological Survey; Estados UnidosFil: Barrientos, Rafael. Universidad Complutense de Madrid; EspañaFil: Bicknell, Jake E.. University of Kent; Reino UnidoFil: Buhl, Deborah A.. United States Geological Survey; Estados UnidosFil: Cebrian, Just. Mississippi State University; Estados UnidosFil: Ceia, Ricardo S.. Universidad de Coimbra; PortugalFil: Cibils Martina, Luciana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Clarke, Sarah. Marine Institute; IrlandaFil: Claudet, Joachim. Universite de Paris; Francia. Centre National de la Recherche Scientifique; FranciaFil: Craig, Michael D.. University of Western Australia; Australia. Murdoch University; AustraliaFil: Davoult, Dominique. Sorbonne University; FranciaFil: De Backer, Annelies. Flanders Research Institute for Agriculture, Fisheries and Food; BélgicaFil: Donovan, Mary K.. University of California; Estados Unidos. University of Hawaii at Manoa; Estados UnidosFil: Eddy, Tyler D.. University of South Carolina; Estados Unidos. Memorial University of Newfoundland; Canadá. Victoria University of Wellington; Nueva ZelandaFil: França, Filipe M.. Lancaster University; Reino UnidoFil: Gardner, Jonathan P. A.. Victoria University of Wellington; Nueva ZelandaFil: Harris, Bradley P.. Alaska Pacific University; Estados UnidosFil: Huusko, Ari. Natural Resources Institute Finland; FinlandiaFil: Jones, Ian L.. Memorial University of Newfoundland; CanadáFil: Kelaher, Brendan P.. Southern Cross University; AustraliaFil: Kotiaho, Janne S.. Universidad de Jyvaskyla; FinlandiaFil: López Baucells, Adrià. Universidad de Lisboa; Portugal. Smithsonian Tropical Research Institute; Panamá. Universidad Nacional de Colombia. Instituto de Investigaciones Amazonicas; Colombia. Museo de Ciencias Naturales de Granollers; EspañaFil: Major, Heather L.. University of New Brunswick; CanadáFil: Mäki Petäys, Aki. Voimalohi Oy; Finlandia. University of Oulu; Finlandi