Charles R. Doss, Jon A. Wellner.

Source: The Annals of Statistics, Volume 47, Number 5, 2950--2976.

Abstract:
We study a likelihood ratio test for the location of the mode of a log-concave density. Our test is based on comparison of the log-likelihoods corresponding to the unconstrained maximum likelihood estimator of a log-concave density and the constrained maximum likelihood estimator where the constraint is that the mode of the density is fixed, say at $m$. The constrained estimation problem is studied in detail in Doss and Wellner (2018). Here, the results of that paper are used to show that, under the null hypothesis (and strict curvature of $-log f$ at the mode), the likelihood ratio statistic is asymptotically pivotal: that is, it converges in distribution to a limiting distribution which is free of nuisance parameters, thus playing the role of the $chi_{1}^{2}$ distribution in classical parametric statistical problems. By inverting this family of tests, we obtain new (likelihood ratio based) confidence intervals for the mode of a log-concave density $f$. These new intervals do not depend on any smoothing parameters. We study the new confidence intervals via Monte Carlo methods and illustrate them with two real data sets. The new intervals seem to have several advantages over existing procedures. Software implementing the test and confidence intervals is available in the R package verb+logcondens.mode+.

Mohamad Elmasri, Maxwell J. Farrell, T. Jonathan Davies, David A. Stephens.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 221--240.

Abstract:
Identifying undocumented or potential future interactions among species is a challenge facing modern ecologists. Recent link prediction methods rely on trait data; however, large species interaction databases are typically sparse and covariates are limited to only a fraction of species. On the other hand, evolutionary relationships, encoded as phylogenetic trees, can act as proxies for underlying traits and historical patterns of parasite sharing among hosts. We show that, using a network-based conditional model, phylogenetic information provides strong predictive power in a recently published global database of host-parasite interactions. By scaling the phylogeny using an evolutionary model, our method allows for biological interpretation often missing from latent variable models. To further improve on the phylogeny-only model, we combine a hierarchical Bayesian latent score framework for bipartite graphs that accounts for the number of interactions per species with host dependence informed by phylogeny. Combining the two information sources yields significant improvement in predictive accuracy over each of the submodels alone. As many interaction networks are constructed from presence-only data, we extend the model by integrating a correction mechanism for missing interactions which proves valuable in reducing uncertainty in unobserved interactions.

Gianluca Mastrantonio, Clara Grazian, Sara Mancinelli, Enrico Bibbona.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2483--2508.

Abstract:
Improved communication systems, shrinking battery sizes and the price drop of tracking devices have led to an increasing availability of trajectory tracking data. These data are often analyzed to understand animal behavior. In this work, we propose a new model for interpreting the animal movent as a mixture of characteristic patterns, that we interpret as different behaviors. The probability that the animal is behaving according to a specific pattern, at each time instant, is nonparametrically estimated using the Logistic-Gaussian process. Owing to a new formalization and the way we specify the coregionalization matrix of the associated multivariate Gaussian process, our model is invariant with respect to the choice of the reference element and of the ordering of the probability vector components. We fit the model under a Bayesian framework, and show that the Markov chain Monte Carlo algorithm we propose is straightforward to implement. We perform a simulation study with the aim of showing the ability of the estimation procedure to retrieve the model parameters. We also test the performance of the information criterion we used to select the number of behaviors. The model is then applied to a real dataset where a wolf has been observed before and after procreation. The results are easy to interpret, and clear differences emerge in the two phases.

Jeffrey Regier, Andrew C. Miller, David Schlegel, Ryan P. Adams, Jon D. McAuliffe, Prabhat.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1884--1926.

Abstract:
We present a new, fully generative model for constructing astronomical catalogs from optical telescope image sets. Each pixel intensity is treated as a random variable with parameters that depend on the latent properties of stars and galaxies. These latent properties are themselves modeled as random. We compare two procedures for posterior inference. One procedure is based on Markov chain Monte Carlo (MCMC) while the other is based on variational inference (VI). The MCMC procedure excels at quantifying uncertainty, while the VI procedure is 1000 times faster. On a supercomputer, the VI procedure efficiently uses 665,000 CPU cores to construct an astronomical catalog from 50 terabytes of images in 14.6 minutes, demonstrating the scaling characteristics necessary to construct catalogs for upcoming astronomical surveys.

Qiwei Li, Xinlei Wang, Faming Liang, Guanghua Xiao.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1708--1732.

Abstract:
With the advance of imaging technology, digital pathology imaging of tumor tissue slides is becoming a routine clinical procedure for cancer diagnosis. This process produces massive imaging data that capture histological details in high resolution. Recent developments in deep-learning methods have enabled us to identify and classify individual cells from digital pathology images at large scale. Reliable statistical approaches to model the spatial pattern of cells can provide new insight into tumor progression and shed light on the biological mechanisms of cancer. We consider the problem of modeling spatial correlations among three commonly seen cells observed in tumor pathology images. A novel geostatistical marking model with interpretable underlying parameters is proposed in a Bayesian framework. We use auxiliary variable MCMC algorithms to sample from the posterior distribution with an intractable normalizing constant. We demonstrate how this model-based analysis can lead to sharper inferences than ordinary exploratory analyses, by means of application to three benchmark datasets and a case study on the pathology images of $188$ lung cancer patients. The case study shows that the spatial correlation between tumor and stromal cells predicts patient prognosis. This statistical methodology not only presents a new model for characterizing spatial correlations in a multitype spatial point pattern conditioning on the locations of the points, but also provides a new perspective for understanding the role of cell–cell interactions in cancer progression.

Y. X. Rachel Wang, Purnamrita Sarkar, Oana Ursu, Anshul Kundaje, Peter J. Bickel.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1511--1536.

Abstract:
Chromosome conformation capture experiments such as Hi-C are used to map the three-dimensional spatial organization of genomes. One specific feature of the 3D organization is known as topologically associating domains (TADs), which are densely interacting, contiguous chromatin regions playing important roles in regulating gene expression. A few algorithms have been proposed to detect TADs. In particular, the structure of Hi-C data naturally inspires application of community detection methods. However, one of the drawbacks of community detection is that most methods take exchangeability of the nodes in the network for granted; whereas the nodes in this case, that is, the positions on the chromosomes, are not exchangeable. We propose a network model for detecting TADs using Hi-C data that takes into account this nonexchangeability. In addition, our model explicitly makes use of cell-type specific CTCF binding sites as biological covariates and can be used to identify conserved TADs across multiple cell types. The model leads to a likelihood objective that can be efficiently optimized via relaxation. We also prove that when suitably initialized, this model finds the underlying TAD structure with high probability. Using simulated data, we show the advantages of our method and the caveats of popular community detection methods, such as spectral clustering, in this application. Applying our method to real Hi-C data, we demonstrate the domains identified have desirable epigenetic features and compare them across different cell types.

Takashi Owada, Omer Bobrowski.

Source: Bernoulli, Volume 26, Number 3, 2275--2310.

Abstract:
In this paper, we study the persistent homology associated with topological crackle generated by distributions with an unbounded support. Persistent homology is a topological and algebraic structure that tracks the creation and destruction of topological cycles (generalizations of loops or holes) in different dimensions. Topological crackle is a term that refers to topological cycles generated by random points far away from the bulk of other points, when the support is unbounded. We establish weak convergence results for persistence diagrams – a point process representation for persistent homology, where each topological cycle is represented by its $({mathit{birth},mathit{death}})$ coordinates. In this work, we treat persistence diagrams as random closed sets, so that the resulting weak convergence is defined in terms of the Fell topology. Using this framework, we show that the limiting persistence diagrams can be divided into two parts. The first part is a deterministic limit containing a densely-growing number of persistence pairs with a shorter lifespan. The second part is a two-dimensional Poisson process, representing persistence pairs with a longer lifespan.

Arnak S. Dalalyan, Lionel Riou-Durand.

Source: Bernoulli, Volume 26, Number 3, 1956--1988.

Abstract:
Langevin diffusion processes and their discretizations are often used for sampling from a target density. The most convenient framework for assessing the quality of such a sampling scheme corresponds to smooth and strongly log-concave densities defined on $mathbb{R}^{p}$. The present work focuses on this framework and studies the behavior of the Monte Carlo algorithm based on discretizations of the kinetic Langevin diffusion. We first prove the geometric mixing property of the kinetic Langevin diffusion with a mixing rate that is optimal in terms of its dependence on the condition number. We then use this result for obtaining improved guarantees of sampling using the kinetic Langevin Monte Carlo method, when the quality of sampling is measured by the Wasserstein distance. We also consider the situation where the Hessian of the log-density of the target distribution is Lipschitz-continuous. In this case, we introduce a new discretization of the kinetic Langevin diffusion and prove that this leads to a substantial improvement of the upper bound on the sampling error measured in Wasserstein distance.

Holger Sambale, Arthur Sinulis.

Source: Bernoulli, Volume 26, Number 3, 1863--1890.

Abstract:
We derive sufficient conditions for a probability measure on a finite product space (a spin system ) to satisfy a (modified) logarithmic Sobolev inequality. We establish these conditions for various examples, such as the (vertex-weighted) exponential random graph model, the random coloring and the hard-core model with fugacity. This leads to two separate branches of applications. The first branch is given by mixing time estimates of the Glauber dynamics. The proofs do not rely on coupling arguments, but instead use functional inequalities. As a byproduct, this also yields exponential decay of the relative entropy along the Glauber semigroup. Secondly, we investigate the concentration of measure phenomenon (particularly of higher order) for these spin systems. We show the effect of better concentration properties by centering not around the mean, but around a stochastic term in the exponential random graph model. From there, one can deduce a central limit theorem for the number of triangles from the CLT of the edge count. In the Erdős–Rényi model the first-order approximation leads to a quantification and a proof of a central limit theorem for subgraph counts.

Ester Mariucci, Kolyan Ray, Botond Szabó.

Source: Bernoulli, Volume 26, Number 2, 1070--1097.

Abstract:
The estimation of a log-concave density on $mathbb{R}$ is a canonical problem in the area of shape-constrained nonparametric inference. We present a Bayesian nonparametric approach to this problem based on an exponentiated Dirichlet process mixture prior and show that the posterior distribution converges to the log-concave truth at the (near-) minimax rate in Hellinger distance. Our proof proceeds by establishing a general contraction result based on the log-concave maximum likelihood estimator that prevents the need for further metric entropy calculations. We further present computationally more feasible approximations and both an empirical and hierarchical Bayes approach. All priors are illustrated numerically via simulations.

Genetic genealogy -- Handbooks, manuals, etc.

Rungie (Family)

Aliaksandr Hubin, Geir Storvik, Florian Frommlet.

Source: Bayesian Analysis, Volume 15, Number 1, 263--333.

Abstract:
Logic regression was developed more than a decade ago as a tool to construct predictors from Boolean combinations of binary covariates. It has been mainly used to model epistatic effects in genetic association studies, which is very appealing due to the intuitive interpretation of logic expressions to describe the interaction between genetic variations. Nevertheless logic regression has (partly due to computational challenges) remained less well known than other approaches to epistatic association mapping. Here we will adapt an advanced evolutionary algorithm called GMJMCMC (Genetically modified Mode Jumping Markov Chain Monte Carlo) to perform Bayesian model selection in the space of logic regression models. After describing the algorithmic details of GMJMCMC we perform a comprehensive simulation study that illustrates its performance given logic regression terms of various complexity. Specifically GMJMCMC is shown to be able to identify three-way and even four-way interactions with relatively large power, a level of complexity which has not been achieved by previous implementations of logic regression. We apply GMJMCMC to reanalyze QTL (quantitative trait locus) mapping data for Recombinant Inbred Lines in Arabidopsis thaliana and from a backcross population in Drosophila where we identify several interesting epistatic effects. The method is implemented in an R package which is available on github.

Lutz F. Gruber, Erica F. Stuber, Lyndsie S. Wszola, Joseph J. Fontaine.

Source: Bayesian Analysis, Volume 14, Number 4, 1173--1199.

Abstract:
We present an integrated open population model where the population dynamics are defined by a differential equation, and the related statistical model utilizes a Poisson binomial convolution likelihood. Key advantages of the proposed approach over existing open population models include the flexibility to predict related, but unobserved quantities such as total immigration or emigration over a specified time period, and more computationally efficient posterior simulation by elimination of the need to explicitly simulate latent immigration and emigration. The viability of the proposed method is shown in an in-depth analysis of outdoor recreation participation on public lands, where the surveyed populations changed rapidly and demographic population closure cannot be assumed even within a single day.

Ioannis Ntzoufras, Claudia Tarantola, Monia Lupparelli.

Source: Bayesian Analysis, Volume 14, Number 3, 797--823.

Abstract:
We introduce a novel Bayesian approach for quantitative learning for graphical log-linear marginal models. These models belong to curved exponential families that are difficult to handle from a Bayesian perspective. The likelihood cannot be analytically expressed as a function of the marginal log-linear interactions, but only in terms of cell counts or probabilities. Posterior distributions cannot be directly obtained, and Markov Chain Monte Carlo (MCMC) methods are needed. Finally, a well-defined model requires parameter values that lead to compatible marginal probabilities. Hence, any MCMC should account for this important restriction. We construct a fully automatic and efficient MCMC strategy for quantitative learning for such models that handles these problems. While the prior is expressed in terms of the marginal log-linear interactions, we build an MCMC algorithm that employs a proposal on the probability parameter space. The corresponding proposal on the marginal log-linear interactions is obtained via parameter transformation. We exploit a conditional conjugate setup to build an efficient proposal on probability parameters. The proposed methodology is illustrated by a simulation study and a real dataset.

Chao Du, S. C. Kou.

Source: Statistical Science, Volume 35, Number 1, 75--91.

Abstract:
Toward the last quarter of the 20th century, the emergence of single-molecule experiments enabled scientists to track and study individual molecules’ dynamic properties in real time. Unlike macroscopic systems’ dynamics, those of single molecules can only be properly described by stochastic models even in the absence of external noise. Consequently, statistical methods have played a key role in extracting hidden information about molecular dynamics from data obtained through single-molecule experiments. In this article, we survey the major statistical methodologies used to analyze single-molecule experimental data. Our discussion is organized according to the types of stochastic models used to describe single-molecule systems as well as major experimental data collection techniques. We also highlight challenges and future directions in the application of statistical methodologies to single-molecule experiments.

Yazhen Wang, Xinyu Song.

Source: Statistical Science, Volume 35, Number 1, 51--74.

Abstract:
Quantum science and quantum technology are of great current interest in multiple frontiers of many scientific fields ranging from computer science to physics and chemistry, and from engineering to mathematics and statistics. Their developments will likely lead to a new wave of scientific revolutions and technological innovations in a wide range of scientific studies and applications. This paper provides a brief review on quantum communication, quantum information, quantum computation, quantum simulation, and quantum metrology. We present essential quantum properties, illustrate relevant concepts of quantum science and quantum technology, and discuss their scientific developments. We point out the need for statistical analysis in their developments, as well as their potential applications to and impacts on statistics and data science.

Daniele Durante, Tommaso Rigon.

Source: Statistical Science, Volume 34, Number 3, 472--485.

Abstract:
Variational Bayes (VB) is a common strategy for approximate Bayesian inference, but simple methods are only available for specific classes of models including, in particular, representations having conditionally conjugate constructions within an exponential family. Models with logit components are an apparently notable exception to this class, due to the absence of conjugacy among the logistic likelihood and the Gaussian priors for the coefficients in the linear predictor. To facilitate approximate inference within this widely used class of models, Jaakkola and Jordan ( Stat. Comput. 10 (2000) 25–37) proposed a simple variational approach which relies on a family of tangent quadratic lower bounds of the logistic log-likelihood, thus restoring conjugacy between these approximate bounds and the Gaussian priors. This strategy is still implemented successfully, but few attempts have been made to formally understand the reasons underlying its excellent performance. Following a review on VB for logistic models, we cover this gap by providing a formal connection between the above bound and a recent Pólya-gamma data augmentation for logistic regression. Such a result places the computational methods associated with the aforementioned bounds within the framework of variational inference for conditionally conjugate exponential family models, thereby allowing recent advances for this class to be inherited also by the methods relying on Jaakkola and Jordan ( Stat. Comput. 10 (2000) 25–37).

Subhash Kulkarni
Oct 31, 2018; 38:9346-9354
Symposium and Mini-Symposium

Benjamin E. Reese
Mar 2, 2005; 25:2167-2175
BehavioralSystemsCognitive

Fabrizio Benedetti
Nov 9, 2005; 25:10390-10402
Symposia and Mini-Symposia

Ben Warren
Apr 8, 2020; 40:3130-3140
Neurobiology of Disease

KM Harris
Jul 1, 1992; 12:2685-2705
Articles

Gregor Thut
Sep 13, 2006; 26:9494-9502
BehavioralSystemsCognitive

French translation of the Basel Committee is publishing "Sound Practices: implications of fintech developments for banks and bank supervisors", February 2018.

Spanish translation of the BIS press release on the presentation of the Annual Economic Report 2018, 24 June 2018. Las autoridades pueden prolongar el actual repunte económico más allá del corto plazo aplicando reformas estructurales, reconstruyendo el espacio de las políticas monetaria y fiscal para afrontar futuras amenazas y fomentando una pronta implementación de las reformas reguladoras, sostiene el Banco de Pagos Internacionales (BPI) en su Informe Económico Anual. ...

Keynote speech by Mr Agustín Carstens, General Manager of the BIS, at the 55th SEACEN Governors' Conference and High-level Seminar on "Data and technology: embracing innovation", Singapore, 14 November 2019.

Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by overstimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterization of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterize a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties of the auditory receptors remain unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialized receptor lymph that bathes the auditory receptors, revealing striking parallels with the mammalian auditory system.

SIGNIFICANCE STATEMENT Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive sound-induced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to, for the first time in any animal, characterize changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something that we show rings true for invertebrate ears too.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.

SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.

The Drosophila nervous system is ensheathed by a layer of outer glial cells, the perineurial glia, and a specialized extracellular matrix, the neural lamella. The function of perineurial glial cells and how they interact with the extracellular matrix are just beginning to be elucidated. Integrin-based focal adhesion complexes link the glial membrane to the extracellular matrix, but little is known about integrin's regulators in the glia. The transmembrane Ig domain protein Basigin/CD147/EMMPRIN is highly expressed in the perineurial glia surrounding the Drosophila larval nervous system. Here we show that Basigin associates with integrin at the focal adhesions to uphold the structure of the glia-extracellular matrix sheath. Knockdown of Basigin in perineurial glia using RNAi results in significant shortening of the ventral nerve cord, compression of the glia and extracellular matrix in the peripheral nerves, and reduction in larval locomotion. We determined that Basigin is expressed in close proximity to integrin at the glial membrane, and that expression of the extracellular integrin-binding domain of Basigin is sufficient to rescue peripheral glial compression. We also found that a reduction in expression of integrin at the membrane rescues the ventral nerve cord shortening, peripheral glial compression, and locomotor phenotypes, and that reduction in the integrin-binding protein Talin can partially rescue glial compression. These results identify Basigin as a potential negative regulator of integrin in the glia, supporting proper glial and extracellular matrix ensheathment of the nervous system.

SIGNIFICANCE STATEMENT The glial cells and extracellular matrix play important roles in supporting and protecting the nervous system, but the interactions between these components have not been well characterized. Our study identified expression of a conserved Ig superfamily protein, Basigin, at the glial membrane of Drosophila where it associates with the integrin-based focal adhesion complexes to ensure proper ensheathment of the CNS and PNS. Loss of Basigin in the glia results in an overall compression of the nervous system due to integrin dysregulation, which causes locomotor defects in the animals. This underlies the importance of glia-matrix communication for structural and functional support of the nervous system.

Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.

SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.

Some of the most innovative ways being used to improve agricultural practices involve nuclear technology. Nuclear applications in agriculture rely on the use of isotopes and radiation techniques to combat pests and diseases, increase crop production, protect land and water resources, ensure food safety and authenticity, and increase livestock production. FAO and the International Atomic Energy Agency (IAEA) have been expanding [...]

The burial site, which contains remains from both the Picts and the Norse, is at risk of disappearing due to coastal erosion

The missionary who lived in the house during the mid-1800s delivered vaccinations to locals during a smallpox epidemic

The liquid inside is 3 percent alcohol by volume—and contains 0.13 milligrams of lead per liter

New research details the first forensic investigation of the Sylt concentration camp, located on the Channel Island of Alderney, since the end of WWII

Researchers lifted the ancient Egyptian mummy out of her coffin for the first time in 100 years and, to their surprise, uncovered the ancient artworks

The Archaeological Institute of America launched its Build Your Own Monument challenge early to inspire families quarantining at home

The controversial series stems from the museum's desire to reach a younger generation by telling history in new ways

The find could help pin down when the South Pole turned icy

The 18th-century Edinburgh factory once produced a million bottles a week

The story behind the image, and its removal, led to mixed reactions from the public, including native communities

By building a new broch, the project aims to better understand how and why the original structures were constructed

The ancient Egyptian girl was only 15 or 16 years old when she died

Airing on the aquarium's Twitch channel at 4 p.m. EST today, the two-hour session will focus on the video game's diverse insect population