FGFs: Neurodevelopment’s Jack-of-all-Trades – How Do They Do it?

From neurulation to postnatal processes, the requirements for FGF signaling in many aspects of neural precursor cell biology have been well documented. However, identifying a requirement for FGFs in a particular neurogenic process provides only an initial and superficial understanding of what FGF signaling is doing. How FGFs specify cell types in one instance, yet promote cell survival, proliferation, migration, or differentiation in other instances remains largely unknown and is key to understanding how they function. This review describes what we have learned primarily from in vivo vertebrate studies about the roles of FGF signaling in neurulation, anterior–posterior patterning of the neural plate, brain patterning from local signaling centers, and finally neocortex development as an example of continued roles for FGFs within the same brain area. The potential explanations for the diverse functions of FGFs through differential interactions with cell intrinsic and extrinsic factors is then discussed with an emphasis on how little we know about the modulation of FGF signaling in vivo. A clearer picture of the mechanisms involved is nevertheless essential to understand the behavior of neural precursor cells and to potentially guide their fates for therapeutic purposes

Targeting of cre to the Foxg1 (BF-1) Locus Mediates loxP Recombination in the Telencephalon and Other Developing Head Structures

AbstractThe use of genetics to study the development of the telencephalon and derivatives such as the cerebral cortex has been limited. The telencephalon begins to form midway through gestation, and targeted mutations in genes suspected of playing roles in its development often lead to early phenotypes that preclude analysis of their role at later stages. This problem can be circumvented using a Cre/loxP recombination system. A mouse line was produced in which cre was targeted to the Foxg1 (BF-1) locus, a gene expressed specifically in the telencephalon and discrete head structures. Crosses between Foxg1–Cre mice and three separate loxP reporter mice generated embryos with recombination patterns matching that expected from the normal pattern of Foxg1 expression. Recombination occurs invariably in the telencephalon, anterior optic vesicle, otic vesicle, facial and head ectoderm, olfactory epithelium, mid–hindbrain junction, and pharyngeal pouches. Recombination in some animals also occurs less efficiently in tissues not known to express Foxg1. We show that the genetic background of the parental mice and the loxP target allele can each contribute to differences in the exact pattern of recombination. Collectively, these data show that Foxg1–Cre mice should be useful in the deletion or ectopic expression of any floxed target gene in a Foxg1-like pattern

Accurately summarizing an outbreak using epidemiological models takes time

Recent outbreaks of monkeypox and Ebola, and worrying waves of COVID-19, influenza and respiratory syncytial virus, have all led to a sharp increase in the use of epidemiological models to estimate key epidemiological parameters. The feasibility of this estimation task is known as the practical identifiability (PI) problem. Here, we investigate the PI of eight commonly reported statistics of the classic Susceptible-Infectious-Recovered model using a new measure that shows how much a researcher can expect to learn in a model-based Bayesian analysis of prevalence data. Our findings show that the basic reproductive number and final outbreak size are often poorly identified, with learning exceeding that of individual model parameters only in the early stages of an outbreak. The peak intensity, peak timing, and initial growth rate are better identified, being in expectation over 20 times more probable having seen the data by the time the underlying outbreak peaks. We then test PI for a variety of true parameter combinations, and find that PI is especially problematic in slow-growing or less-severe outbreaks. These results add to the growing body of literature questioning the reliability of inferences from epidemiological models when limited data are available.Comment: 7 pages, 4 figure

A shadowing problem in the detection of overlapping communities: lifting the resolution limit through a cascading procedure

Community detection is the process of assigning nodes and links in significant communities (e.g. clusters, function modules) and its development has led to a better understanding of complex networks. When applied to sizable networks, we argue that most detection algorithms correctly identify prominent communities, but fail to do so across multiple scales. As a result, a significant fraction of the network is left uncharted. We show that this problem stems from larger or denser communities overshadowing smaller or sparser ones, and that this effect accounts for most of the undetected communities and unassigned links. We propose a generic cascading approach to community detection that circumvents the problem. Using real and artificial network datasets with three widely used community detection algorithms, we show how a simple cascading procedure allows for the detection of the missing communities. This work highlights a new detection limit of community structure, and we hope that our approach can inspire better community detection algorithms.Comment: 14 pages, 12 figures + supporting information (5 pages, 6 tables, 3 figures

A photobiological approach to biophilic design in extreme climates

This paper proposes the biophilic design approach as a plausible hypothesis for the challenging conditions related to living and working in extreme cold climates. Biophilic design has recently been developed to overcome the adverse effects of the built environment and to improve human well-being by redefining the human-nature relationship. Yet, biophilic design should be adapted to extreme cold climates in order to meet the biological needs of people in northern territories. This issue becomes more important when considering the availability of natural light due to the strong seasonal photoperiod and its effects on human well-being in such regions. The present paper critically reviews biophilic design patterns and identifies their main shortcomings. These shortcomings include the lack of (1) recommendations applicable to extreme cold climates (2) adaptation to the local photoperiods, and (3) a systemic framework integrated into the design process. The paper draws attention to the image-forming and non-image-forming effects of light as a basis of the human-nature design approach. In this regard, photobiological outcomes have been reviewed. Then, the paper discusses the existing lighting standards and guidelines in North America and how they have mainly been developed to fulfil the image-forming demands for light. Further efforts are needed to revise these standards with respect to the non-image-forming effects of light and the biophilic design requirements. Finally, adaptive building envelopes are presented as a hypothetical solution to optimize the biophilic qualities of buildings and address the biological needs of people living and working in extreme cold climates in northern territories

Biophilic, photobiological and energy-efficient design framework of adaptive building façades for Northern Canada

This paper develops an integrated design framework of adaptive building façades (ABFs) to respond to photobiological and thermal needs of occupants, biophilic factors, energy requirements and climatic features in Northern Canada, i.e. near and above 50°N. The paper discusses the importance of biophilic and photobiological factors and ABFs to improve occupants’ health and human-nature relations and deal with the extreme climate in Northern Canada where non-adapted buildings that could negatively affect occupants’ wellbeing. The paper shows that existing ABFs must be further developed for northern applications in terms of (i) the physical structure and configuration of components (ii) the design of solar shading/louver panels to address photobiological and biophilic requirements (iii) the development of lighting adaptation scenarios to respond to biophilic and photobiological needs, local photoperiods and energy issues, and (iv) the overall biophilic quality for accessibility to natural patterns. The ABFs’ framework was developed in three phases including (1) process environmental data (2) produce adaptation scenarios, and (3) operate adaptation scenarios. The research discussed major issues of all phases that must be further studied, especially the development of hourly/daily/seasonally lighting adaptation scenarios. The paper develops a holistic parametric methodology to integrate and optimize major design variables of ABF’s components

SMAD4 is essential for generating subtypes of neurons during cerebellar development

AbstractCerebellum development involves the coordinated production of multiple neuronal cell types. The cerebellar primordium contains two germinative zones, the rhombic lip (RL) and the ventricular zone (VZ), which generate different types of glutamatergic and GABAergic neurons, respectively. What regulates the specification and production of glutamatergic and GABAergic neurons as well as the subtypes for each of these two broad classes remains largely unknown. Here we demonstrate with conditional genetic approaches in mice that SMAD4, a major mediator of BMP and TGFβ signaling, is required early in cerebellar development for maintaining the RL and generating subsets of RL-derived glutamatergic neurons, namely neurons of the deep cerebellar nuclei, unipolar brush cells, and the late cohort of granule cell precursors (GCPs). The early cohort of GCPs, despite being deficient for SMAD4, is still generated. In addition, the numbers of GABAergic neurons are reduced in the mutant and the distribution of Purkinje cells becomes abnormal. These studies demonstrate a temporally and spatially restricted requirement for SMAD4 in generating subtypes of cerebellar neurons

Spatial epidemiology and adaptive targeted sampling to manage the Chagas disease vector Triatoma dimidiata

Widespread application of insecticide remains the primary form of control for Chagas disease in Central America, despite only temporarily reducing domestic levels of the endemic vector Triatoma dimidiata and having little long-term impact. Recently, an approach emphasizing community feedback and housing improvements has been shown to yield lasting results. However, the additional resources and personnel required by such an intervention likely hinders its widespread adoption. One solution to this problem would be to target only a subset of houses in a community while still eliminating enough infestations to interrupt disease transfer. Here we develop a sequential sampling framework that adapts to information specific to a community as more houses are visited, thereby allowing us to efficiently find homes with domiciliary vectors while minimizing sampling bias. The method fits Bayesian geostatistical models to make spatially informed predictions, while gradually transitioning from prioritizing houses based on prediction uncertainty to targeting houses with a high risk of infestation. A key feature of the method is the use of a single exploration parameter, $\alpha$, to control the rate of transition between these two design targets. In a simulation study using empirical data from five villages in southeastern Guatemala, we test our method using a range of values for $\alpha$, and find it can consistently select fewer homes than random sampling, while still bringing the village infestation rate below a given threshold. We further find that when additional socioeconomic information is available, much larger savings are possible, but that meeting the target infestation rate is less consistent, particularly among the less exploratory strategies. Our results suggest new options for implementing long-term T. dimidiata control

Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness

Gouin, J.-P., Zhou, Q. Q., Booij, L., Boivin, M., Côté, S. M., Hébert, M., Ouellet-Morin, I., Szyf, M., Tremblay, R. E., Turecki, G. & Vitaro, F. (2017) Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Scientific Reports, 7(1), 1-14 (7446).Recent models propose deoxyribonucleic acid methylation of key neuro-regulatory genes as a molecular mechanism underlying the increased risk of mental disorder associated with early life adversity (ELA). The goal of this study was to examine the association of ELA with oxytocin receptor gene (OXTR) methylation among young adults. Drawing from a 21-year longitudinal cohort, we compared adulthood OXTR methylation frequency of 46 adults (23 males and 23 females) selected for high or low ELA exposure based on childhood socioeconomic status and exposure to physical and sexual abuse during childhood and adolescence. Associations between OXTR methylation and teacher-rated childhood trajectories of anxiousness were also assessed. ELA exposure was associated with one significant CpG site in the first intron among females, but not among males. Similarly, childhood trajectories of anxiousness were related to one significant CpG site within the promoter region among females, but not among males. This study suggests that females might be more sensitive to the impact of ELA on OXTR methylation than males

Early uneven ear input induces long-lasting differences in left-right motor function

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear±induced striatal asymmetries identified here intersect with non±ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left±right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input. Despite a long-standing fascination with asymmetries in left±right brain function, very little is known about the causes of functional brain asymmetry in mammals, which appear independent of the mechanisms that create anatomical asymmetries during development. Asymmetries in motor function are a common example and include preferred turning direction, handedness, and footedness. In this study, using mouse models, we establish a causal link between transient imbalances in degenerating inner ear function and the establishment of stable asymmetries in neural pathways that regulate motor activity and in motor behavior. Our study also suggests that shared mechanisms may underlie lateralized motor behaviors across mammalian species. For example, we show that in humans with normal ear function, the strength of the vestibular response from each ear in the forebrain correlates with asymmetric motor behavior, measured as handedness. In a broader sense, our study reveals a conceptually novel role for sensory input in shaping the asymmetric distribution of brain function, a process for which there is otherwise no clear mechanism